“What is the physiology of body fluids?”

One of the major functions of the kidneys is to maintain the volume and composition of the body’s fluids constant despite wide variations in the daily intake of water and solutes.

Physiology Of Body Fluids chapter, the volume, and composition of the body’s fluids are discussed to provide a background for the study of the kidneys as regulatory organs.

Some of the basic principles, terminology, and concepts related to the properties of solutes in solution also are reviewed.

Physicochemical Properties Of Electrolyte Solutions

“Importance of studying the physiology of body fluids”

Molarity and Equivalence

The amount of a substance dissolved in a solution (i.e., its concentration) is expressed in terms of either molarity or equivalence. Molarity is the amount of a substance relative to its molecular weight.

For example, glucose has a molecular weight of 180 g/mol. If 1 L of water contains 1 g of glucose, the molarity of this glucose solution would be determined as:

⇒ \(\frac{1 \mathrm{~g} / \mathrm{L}}{180 \mathrm{~g} / \mathrm{mol}}=0.0056 \mathrm{~mol} / \mathrm{L} \text { or } 5.6 \mathrm{mmol} / \mathrm{L}\) → (1)

For uncharged molecules, such as glucose and urea, concentrations in the body fluids are usually expressed in terms of molarity.

Because many of the substances of biological interest are present at very low concentrations, units are more frequently expressed in the millimolar range (mmol/L).

“Common components of body fluids explained”

The concentration of solutes, which normally dissociate into more than one particle when dissolved in solution (For example., sodium chloride [NaCl]), is usually expressed in terms of equivalence.

Equivalence refers to the stoichiometry of the interaction between cation and anion and is determined by the valence of these ions.

For example, consider a 1 L solution containing 9 g of NaCl (molecular weight = 58.4 g/mol). The molarity of this solution is 154 mmol/L.

Because NaCl dissociates into Na+ and Cl^– ions, and assuming complete dissociation, this solution contains 154 mmol/L of Na^-+ and 154 mmol/L of Cl^–.

Because the valence of these ions is 1, these concentrations also can be expressed as milliequivalents (mEq) of the ion per liter (i.e., 154 mEq/L for Na⁺ and Cl^–, respectively).

For univalent ions such as Na+ and Cl^–, concentrations expressed in terms of molarity and equivalence are identical. However, this is not true for ions having valences greater than 1.

Accordingly, the concentration of Ca⁺⁺ (molecular weight = 40.1 g/mol and valence = 2) in a 1 L solution containing 0.1 g of this ion could be expressed as:

⇒ \(\frac{0.1 \mathrm{~g} / \mathrm{L}}{40.1 \mathrm{~g} / \mathrm{mol}}=2.5 \mathrm{mmol} / \mathrm{L}\) → (2)

= 2.5 mmol/L × 2 Eq/mol = 5 mEq

Although some exceptions exist, it is customary to express concentrations of ions in milliequivalents per liter (mEq/L).

“Role of electrolytes in body fluid physiology”

Osmosis And Osmotic Pressure

The movement of water across cell membranes occurs by the process of osmosis. The driving force for this movement is the osmotic pressure difference across the cell membrane.

Illustrates the concept of osmosis and the measurement of the osmotic pressure of a solution.

Osmotic pressure is determined solely by the number of solute particles in the solution. It is not dependent on factors such as the size of the solute particles, their mass, or their chemical nature (For Example., valence).

Osmotic pressure (π), measured in atmospheres (atm), is calculated by van’t Hoff’s law as follows:

π = nCRT → (3)

where n is the number of dissociable particles per molecule, C is total solute concentration, R is gas constant, and T is temperature in degrees Kelvin (°K).

For a molecule that does not dissociate in water, such as glucose or urea, a solution containing mmol/L of these solutes at 37° C can exert an osmotic pressure of 2.54 x 10^-2 atm as calculated by equation 1-3 using the following values: n is 1, C is 0.001 mol/L, R is 0.082 atm L/mol, and T is 310° K.

“Functions of intracellular vs extracellular fluids”

Because 1 atm equals 760 mm Hg at sea level, π for this solution also can be expressed as 19.3 mm Hg.

Alternatively, osmotic pressure is expressed in terms of osmolarity (see the following discussion). Thus a solution containing 1 mmol/L of solute particles exerts an osmotic pressure of 1 milliosmole/L (1 mOsm/L).

For substances that dissociate in a solution, n of equation 3 has a value other than 1.

For example, a 150 mmol/L solution of NaCl has an osmolarity of 300 mOsm/L because each molecule of NaCl dissociates into a Na⁺ and a Cl^– ion (i.e., n = 2).

If the dissociation of a substance into its component ions is not complete, n is not an integer. Accordingly, osmolarity for any solution can be calculated as:

Osmolarity= Concentration × Number of dissociable particles → (2)

mOsm/L = mmol/L × number of particles/mol

“Importance of sodium and potassium in body fluids”

“How does water distribution affect body fluid balance?”

Osmolarity And Osmolality

Osmolarity and osmolality are frequently confused and incorrectly interchanged. Osmolarity refers to the number of solute particles per 1 L of solvent, whereas osmolality is the number of solute particles in 1 kg of solvent.

For dilute solutions, the difference between osmolarity and osmolality is insignificant. Measurements of osmolarity are temperature dependent because the volume of solvent varies with temperature (i.e., the volume is larger at higher temperatures).

In contrast, osmolality, which is based on the mass of the solvent, is temperature-independent. For this reason, osmolality is the preferred term for biological systems and is used throughout this and subsequent chapters.

Osmolality has the units of Osm/kg H₂O. Because of the dilute nature of physiologic solutions and because water is the solvent, osmolalities are expressed as milliosmoles per kilogram of water (mOsm/kg H₂O).

Shows the relationships among molecular weight, equivalence, and osmoles for several physiologically significant solutes.

“Role of plasma in maintaining fluid homeostasis”

“Mechanisms of fluid balance in the body”

Tonicity

The tonicity of a solution is related to its effect on the volume of a cell. Solutions that do not change the volume of a cell are said to be isotonic.

A hypotonic solution causes a cell to swell, whereas a hypertonic solution causes a cell to shrink.

Although it is related to osmolality, tonicity also takes into consideration the ability of the solute to cross the cell membrane.

Consider two solutions: a 300 mmol/L solution of sucrose and a 300 mmol/L solution of urea. Both solutions have an osmolality of 300 mOsm/kg H₂O and therefore are said to be isosmotic (i.e., they have the same osmolality).

When red blood cells (which, for the purpose of this illustration, also have an intracellular fluid osmolality of 300 mOsm/kg H₂O) are placed in the two solutions.

Those in the sucrose solution maintain their normal volume, but those placed in urea swell and eventually burst. Thus the sucrose solution is isotonic and the urea solution is hypotonic.

The differential effect of these solutions on red cell volume is related to the permeability of the plasma membrane to sucrose and urea.

The red blood cell membrane contains uniporters for urea. Thus urea easily crosses the cell membrane (i.e., the membrane is permeable to urea), driven by the concentration gradient (i.e., extracellular [urea] > intracellular [urea]).

In contrast, the red blood cell membrane does not contain sucrose transporters, and sucrose cannot enter the cell (i.e., the membrane is impermeable to sucrose).

A solute must not permeate the red blood cell membrane to exert an osmotic pressure across a membrane because it is impermeable to sucrose when exerting an osmotic pressure.

It exerts an osmotic pressure equal to and opposite to the osmotic pressure generated by the contents of the red blood cell (in this case, 300 mOsm/kg H₂O).

In contrast, urea is readily able to cross the red blood cell membrane, and it cannot exert an osmotic pressure to balance that generated by the intracellular solutes of the red blood cell.

“Role of kidneys in regulating body fluids”

Consequently, sucrose is termed an effective osmole and urea is termed an ineffective osmole. To take into account the effect of a solute’s membrane permeability on osmotic pressure, it is necessary to rewrite equation 1-3 as:

π = σ (nCRT) → (5)

where σ is the reflection coefficient or osmotic coefficient and is a measure of the relative ability of the solute to cross a cell membrane.

For a solute that can freely cross the cell membrane (such as urea in this example), σ = 0, and no effective osmotic pressure is exerted. Thus urea is an ineffective osmole for red blood cells.

In contrast, σ = 1 for a solute that cannot cross the cell membrane (i.e., sucrose). Such a substance is said to be an effective osmole.

Many solutes are neither completely able nor completely unable to cross cell membranes (i.e., 0 < σ < 1) and generate an osmotic pressure that is only a fraction of what is expected from the total solute concentration.

“How does ADH (antidiuretic hormone) affect fluid balance?”

Oncotic Pressure

The oncotic pressure is the osmotic pressure generated by large molecules (especially proteins) in solution. As illustrated in Figure 1-2, the magnitude of the osmotic pressure generated by a solution of protein does not conform to van’t Hoff’s law.

The cause of this anomalous relationship between protein concentration and osmotic pressure is not completely understood but appears to be related to the size and shape of the protein molecule.

For example, the correlation to can’t Hoff’s law is more precise with small, globular proteins than with larger protein molecules.

The oncotic pressure exerted by proteins in human plasma has a normal value of approximately 26 to 28 mm Hg.

However, this pressure appears to be small when considered in terms of osmotic pressure (28 mm Hg ≈ 1.4 mOsm/kg H₂O).

It is an important force involved in fluid movement across capillaries (details of this topic are presented in the following section on fluid exchange between body fluid compartments).

Specific Gravity

The total solute concentration in a solution also can be measured as specific gravity. Specific gravity is defined as the weight of a volume of solution divided by the weight of an equal volume of distilled water.

Thus the specific gravity of distilled water is 1. Because biological fluids contain a number of different substances, their specific gravities are greater than 1. For example, normal human plasma has a specific gravity in the range of 1.008 to 1.010.

Volumes Of Body Fluid Compartments

“Impact of aldosterone on body fluid regulation”

Water makes up approximately 60% of the body’s weight, with variability among individuals being a function of the amount of adipose tissue that is present.

Because the water content of adipose tissue is lower than that of other tissue, increased amounts of adipose tissue reduce the fraction of total body weight attributed to water.

The specific gravity of urine is sometimes measured in clinical settings and used to assess the concentrating ability of the kidney. The specific gravity of urine varies in proportion to its osmolality.

However, because specific gravity depends on both the number of solute particles and their weight, the relationship between specific gravity and osmolality is not always predictable.

For example, patients who have been injected with radiocontrast dye (molecular weight >500 g/mol) for radiographic studies can have high values of urine-specific gravity (1.040 to 1.050) even though the urine osmolality is similar to that of plasma (For Example., 300 mOsm/kg H₂O).

The percentage of body weight attributed to water also varies with age. In newborns, it is approximately 75%. This percentage decreases to the adult value of 60% by 1 year of age.

As illustrated, total body water is distributed between two major compartments, which are divided by the cell membrane.

The intracellular fluid (ICF) compartment is the larger compartment and contains approximately two-thirds of the total body water.

The remaining one-third of the body water is contained in the extracellular fluid (ECF) compartment. Expressed as percentages of body weight, the volumes of total body water, ICF, and ECF are:

Total body water = 0.6 × (body weight)
ICF = 0.4 × (body weight)
ECF = 0.2 × (body weight) → (6)

The ECF compartment is further subdivided into interstitial fluid and plasma, which are separated by the capillary wall. The interstitial fluid surrounds the cells in the various tissues of the body and constitutes three-fourths of the ECF volume.

The ECF includes water contained within the bone and dense connective tissue, as well as the cerebrospinal fluid. Plasma represents the remaining one-fourth of the ECF.

Under some pathologic conditions, additional fluid may accumulate in what is referred to as a “third space.”

Third space collections of fluid are part of the ECF and include, for example, the accumulation of fluid in the peritoneal cavity (ascites) of persons with liver disease.

Composition Of Body Fluid Compartments

Sodium is the major cation of the ECF and Cl^– and bicarbonate (HCO^–₃ ) are the major anions.

The ionic composition of the plasma and interstitial fluid compartments of the ECF is similar because they are separated only by the capillary endothelium, a barrier that is freely permeable to small ions.

The major difference between the interstitial fluid and plasma is that the latter contains significantly more protein.

This differential concentration of protein can affect the distribution of cations and anions between these two compartments (i.e., the Donnan effect).

Because plasma proteins have a net negative charge that tends to increase the cation concentrations and reduce the anion concentrations in the plasma compartment.

However, this effect is small, and the ionic compositions of the interstitial fluid and plasma can be considered identical.

Because of its abundance, Na⁺ (and its attendant anions, primarily Cl^– and HCO^–₃ ) is the major determinant of ECF osmolality.

Accordingly, a rough estimate of the ECF osmolality can be obtained by simply doubling the sodium concentration [Na^–].

For example, if the plasma [Na⁺] is 145 mEq/L, the osmolality of plasma and ECF can be estimated as:

Plasma osmolality= 2(plasma [Na⁺]) → (7)

= 290 mOsm/kg H₂O

Because water is in osmotic equilibrium across the capillary endothelium and the plasma membrane of cells, measurement of the plasma osmolality also provides a measure of the osmolality of the ECF and ICF.

In clinical situations, a more accurate estimate of the plasma osmolality is obtained by also considering the contribution of glucose and urea to the plasma osmolality.

Accordingly, plasma osmolality can be estimated as:

⇒ \(\begin{aligned}
& \text { Plasma osmolality } = 2\left(\text { plasma }\left[\mathrm{Na}^{+}\right]\right)+\frac{[\text { glucose }]}{18}+\frac{[\text { urea }]}{2.8}
\end{aligned}\) → (8)

The glucose and urea concentrations are expressed in units of mg/dL (dividing by 18 for glucose and 2.8 for urea allows conversion from the units of mg/dL to mmol/L and thus to mOsm/kg H₂O).

This estimation of plasma osmolality is especially useful when dealing with patients who have an elevated plasma [glucose] level as a result of diabetes mellitus and patients with chronic renal failure whose plasma [urea] level is elevated.

In contrast to the ECF, where the [Na⁺] is approximately 145 mEq/L, the [Na⁺] of the ICF is only 10 to 15 mEq/L. K⁺ is the predominant cation of the ICF, and its concentration is approximately 150 mEq/L.

This asymmetric distribution of Na+ and K+ across the plasma membrane is maintained by the activity of the ubiquitous sodium-potassium–adenosine triphosphatase (Na⁺-K⁺-ATPase) mechanism.

By its action, Na⁺ is extruded from the cell in exchange for K⁺. The anion composition of the ICF differs from that of the ECF.

For example, Cl^– and HCO^–₃ are the predominant anions of the ECF, and organic molecules and the negatively charged groups on proteins are the major anions of the ICF.

“Fluid intake and output: Physiology explained”

Fluid Exchange Between Body Fluid Compartments

Water moves freely and rapidly between the various body fluid compartments. Two forces determine this movement: hydrostatic pressure and osmotic pressure.

Hydrostatic pressure from the pumping of the heart (and the effect of gravity on the column of blood in the vessel) and osmotic pressure exerted by plasma proteins (oncotic pressure) are important determinants of fluid movement across the capillary wall.

By contrast, because hydrostatic pressure gradients are not present across the cell membrane, only osmotic pressure differences between ICF and ECF cause fluid movement into and out of cells.

Capillary Fluid Exchange

The movement of fluid across a capillary wall is determined by the algebraic sum of the hydrostatic and oncotic pressures (the so-called Starling forces) as expressed by the following equation:

⇒ \(\text { Filtration rate }=K_f\left[\left(\mathrm{P}_c-\mathrm{P}_{\mathrm{i}}\right)-\sigma\left(\pi_c-\pi_{\mathrm{i}}\right)\right]\) → (9)

where the filtration rate is the volume of fluid moving across the capillary wall (expressed in units of either volume or capillary surface area or volume/time).

Where K_f is the filtration coefficient of the capillary wall, P_c is hydrostatic pressure within the capillary lumen, π_c is the oncotic pressure of the plasma.

Pi is the hydrostatic pressure of the interstitial fluid, π_i is the oncotic pressure of the interstitial fluid, and σ is the reflection coefficient for proteins across the capillary wall.

The Starling forces for capillary fluid exchange vary between tissues and organs. They also can change in a given capillary bed under physiologic conditions (For Example., exercising muscle) and pathophysiologic conditions (For Example., congestive heart failure).

Illustrates these forces for a capillary bed located in skeletal muscle at rest.

The capillary filtration coefficient (K_f) reflects the intrinsic permeability of the capillary wall to the movement of fluid, as well as the surface area available for filtration.

“Pathophysiology of fluid imbalances explained”

The K_f varies among different capillary beds. For example, the K_f of glomerular capillaries in the kidneys is approximately 100 times greater in magnitude than that of skeletal muscle capillaries.

This difference in K_f accounts for the large volume of fluid filtered across glomerular capillaries compared with the amount filtered across skeletal muscle capillaries.

The hydrostatic pressure within the lumen of a capillary (P_c) is a force promoting the movement of fluid from the lumen into the interstitium.

Its magnitude depends on arterial pressure, venous pressure, and precapillary (arteriolar) and postcapillary (venular and small vein) resistances.

An increase in arterial or venous pressures results in an increase in P_c, whereas a decrease in these pressures has the opposite effect.

Pc increases with either a decrease in precapillary resistance or an increase in postcapillary resistance. Likewise, an increase in precapillary resistance or a decrease in postcapillary resistance decreases P_c.

For virtually all capillary beds, precapillary resistance is greater than postcapillary resistance, and thus the precapillary resistance plays a greater role in determining P_c.

An important exception is the glomerular capillaries, where both precapillary and postcapillary resistances modulate P_c.

The magnitude of P_c varies not only among tissues but also among capillary beds within a given tissue; it also is dependent on the physiologic state of the tissue.

Precapillary sphincters control not only the hydrostatic pressure within an individual capillary but also the number of perfused capillaries in the tissue.

For example, in skeletal muscle at rest, not all capillaries are perfused. During exercise, the relaxation of precapillary sphincters allows perfusion of more capillaries.

The increased number of perfused capillaries reduces the diffusion distance between the cells and capillaries and thereby facilitates the exchange of O₂ and cellular metabolites (For Example., carbon dioxide [CO₂] and lactic acid).

The hydrostatic pressure within the interstitium (P_i) is difficult to measure, but in the absence of edema (i.e., abnormal accumulation of fluid in the interstitium), its value is near zero or slightly negative.

“Emerging research on body fluid regulation”

Thus under normal conditions, it causes fluid to move out of the capillary. However, when edema is present, P_i is positive and it opposes the movement of fluid out of the capillary.

The oncotic pressure of plasma proteins ( π_c) retards the movement of fluid out of the capillary lumen. At a normal plasma protein concentration, π_c has a value of approximately 26 to 28 mm Hg.

The degree to which oncotic pressure influences capillary fluid movement depends on the permeability of the capillary wall to the protein molecules.

If the capillary wall is highly permeable to protein, σ is near zero and the oncotic pressure generated by plasma proteins plays little or no role in capillary fluid exchange.

This situation is seen in the capillaries of the liver (i.e., hepatic sinusoids), which are highly permeable to proteins. As a result, the protein concentration of the interstitial fluid is essentially the same as that of plasma.

In the capillaries of skeletal muscle, σ is approximately 0.9, whereas in the glomeruli of the kidneys, the value is essentially 1.

Therefore plasma protein oncotic pressure plays an important role in fluid movement across these capillary beds.

The protein that leaks across the capillary wall into the interstitium exerts an oncotic pressure ( π_i) and promotes the movement of fluid out of the capillary lumen.

In skeletal muscle capillaries under normal conditions, πi is small and has a value of only 8 mm Hg. As depicted, the balance of Starling forces across muscle capillaries causes fluid to leave the lumen (filtration) along its entire length.

Some of this filtered fluid reenters the vasculature across the postcapillary venule where the Starling forces are reversed (i.e., the net driving force for fluid movement is into the vessel).

The remainder of the filtered fluid is returned to the circulation through the lymphatics. The sinusoids of the liver also filter along their entire length.

In contrast, during the digestion of a meal, the balance of forces across the capillaries of the gastrointestinal tract results in the net uptake of fluid into the capillary.

Normally, 8 to 12 L/day of fluid moves across capillary beds throughout the body and is collected by lymphatic vessels. This lymphatic fluid flows first to lymph nodes, where most of the fluid is returned to circulation.

Fluid not returned to the circulation at the lymph nodes (1 to 4 L/day) reenters the circulation through the thoracic and right lymphatic ducts.

However, under conditions of increased capillary filtration, such as that which occurs in persons with congestive heart failure, thoracic and right lymphatic duct flow can increase 10-fold to 20-fold.

Cellular Fluid Exchange

Osmotic pressure differences between ECF and ICF are responsible for fluid movement between these compartments. Because the plasma membrane of cells contains water channels (aquaporins [AQPs]), water can easily cross the membrane.

Thus a change in the osmolality of either ICF or ECF results in rapid movement (i.e., in minutes) of water between these compartments. Thus, except for transient changes, the ICF and ECF compartments are in osmotic equilibrium.

Water movement across the plasma membrane of cells occurs through a class of integral membrane proteins called aquaporins (AQPs).

Although water can cross the membrane through other transporters (For Example., an Na⁺– glucose symporter), AQPs are the main route of water movement into and out of the cell.

To date, 13 AQPs have been identified. These AQPs can be divided into two subgroups.

One group, which includes the AQP involved in the regulation of water movement across the apical membrane of renal collecting duct cells by arginine vasopressin (AQP-2), is permeable only to water.

The second group is permeable not only to water but also to low-molecular-weight substances, including gases and metalloids.

Because glycerol can cross the membrane via this group of aquaporins, they are termed aquaglyceroporins.

AQPs exist in the plasma membrane as a homotetramer, with each monomer functioning as a water channel.

In contrast to the movement of water, the movement of ions across cell membranes is more variable from cell to cell and depends on the presence of specific membrane transport proteins.

Consequently, as a first approximation, fluid exchange between the ICF and ECF under pathophysiologic conditions can be analyzed by assuming that appreciable shifts of ions between the compartments do not occur.

A useful approach for understanding the movement of fluids between the ICF and the ECF is outlined. To illustrate this approach, consider what happens when solutions containing various amounts of NaCl are added to the ECF.

Principles For Analysis Of Fluid Shifts Between ICF And ECF

The volumes of the various body fluid compartments can be estimated in a healthy adult as shown.

• All exchanges of water and solutes with the external environment occur through the extracellular fluid (ECF) (For Example., intravenous infusion and intake or loss via the gastrointestinal tract).
• Changes in the intracellular fluid (ICF) are secondary to fluid shifts between the ECF and the ICF. Fluid shifts occur only if the perturbation of the ECF alters its osmolality.
• Except for brief periods of seconds to minutes, the ICF and the ECF are in osmotic equilibrium. A measurement of plasma osmolality provides a measure of both the ECF and the ICF osmolality.
• For the sake of simplification, it can be assumed that equilibration between the ICF and the ECF occurs only by the movement of water and not by the movement of osmotically active solutes.
• Conservation of mass must be maintained, especially when considering either the addition or removal of water and or solutes from the body.

Example 1: Addition of Isotonic NaCl to ECF

The addition of an isotonic NaCl solution (For Example., intravenous infusion of 0.9% NaCl:

osmolality ≈290 mOsm/kg H₂O to a patient) to the ECF increases the volume of this compartment by the volume of fluid administered.

Because this fluid has the same osmolality as ECF and therefore also has the same osmolality as ICF, no driving force for fluid movement between these compartments exists, and the volume of ICF is unchanged.

Although Na+ can cross cell membranes, it is effectively restricted to the ECF by the activity of Na⁺-K⁺-ATPase, which is present in the plasma.

Neurosurgical procedures and cerebrovascular accidents (strokes) often result in the accumulation of interstitial fluid in the brain (i.e., edema) and swelling of the neurons.

Because the brain is enclosed within the skull, edema can raise intracranial pressure and thereby disrupt neuronal function, leading to coma and death.

The blood-brain barrier, which separates the cerebrospinal fluid and brain interstitial fluid from the blood, is freely permeable to water but not to most other substances.

As a result, excess fluid in brain tissue can be removed by imposing an osmotic gradient across the blood-brain barrier. Mannitol can be used for this purpose.

Mannitol is a sugar (molecular weight = 182 g/ mol) that does not readily cross the blood-brain barrier and membranes of cells (neurons as well as other cells in the body).

Therefore mannitol is an effective osmole and intravenous infusion results in the movement of fluid from the brain tissue by osmosis.

“Case studies on body fluid physiology outcomes”

Example 2: Addition of Hypotonic NaCl to ECF

The addition of a hypotonic NaCl solution to the ECF (For Example., intravenous infusion of 0.45% NaCl:

osmolality <145 mOsm/kg H₂O to a patient) decreases the osmolality of this fluid compartment, resulting in the movement of water into the ICF.

After osmotic equilibration, the osmolalities of ICF and ECF are equal but lower than before the infusion, and the volume of each compartment is increased. The increase in ECF volume is greater than the increase in ICF volume.

Example 3: Addition of Hypertonic NaCl to ECF

The addition of a hypertonic NaCl solution to the ECF (For Example., intravenous infusion of 3% NaCl:

osmolality ≈1000 mOsm/kg H₂O to a patient) increases the osmolality of this compartment, resulting in the movement of water out of cells.

After osmotic equilibration, the osmolalities of ECF and ICF are equal but higher than before the infusion. The volume of the ECF is increased, whereas that of the ICF is decreased.

Fluid and electrolyte disorders often are seen in clinical practice (For Example., in patients with vomiting and/or diarrhea). In most instances, these disorders are self-limited, and correction of the disorder occurs without the need for intervention.

However, more severe or prolonged disorders may require fluid replacement therapy. Such therapy may be administered orally with special electrolyte solutions, or intravenous fluids may be administered.

Intravenous solutions are available in many formulations. The type of fluid administered to a particular patient is dictated by the patient’s need.

For example, if an increase in the patient’s vascular volume is necessary, a solution containing substances that do not readily cross the capillary wall is infused (For Example., 5% albumin solution).

The oncotic pressure generated by the albumin molecules retains fluid in the vascular compartment, expanding its volume.

Expansion of extracellular fluid (ECF) is accomplished most often by using isotonic saline solutions (For Example., 0.9% sodium chloride [NaCl]).

“Global prevalence of fluid imbalance disorders”

“Complications of ignoring fluid balance issues”

As already noted, administration of an isotonic NaCl solution does not result in the development of an osmotic pressure gradient across the plasma membrane of cells.

Therefore the entire volume of the infused solution remains in the ECF. Patients whose body flids are hyperosmotic need hypotonic solutions.

These solutions may be hypotonic NaCl (For Example., 0.45% NaCl or 5% dextrose in water [D5W]). Administration of D5W is equivalent to an infusion of distilled water because the dextrose is metabolized to CO₂ and water.

The administration of these fluids increases the volumes of both the intracellular fluid (ICF) and ECF.

Finally, patients whose body fluids are hypotonic need hypertonic solutions, which typically are solutions that contain NaCl (For Example., 3% and 5% NaCl).

These solutions expand the volume of the ECF but decrease the volume of the ICF.

Other constituents, such as electrolytes (For Example., K⁺) or drugs, can be added to intravenous solutions to tailor the therapy to the patient’s fluid, electrolyte, and metabolic needs.

The post Physiology Of Body Fluids appeared first on BDS Notes.

“What is the physiology of diuretic action?”

Diuretics, as the name implies, are drugs that cause an increase in urine output. It is important, however, to distinguish this diuresis from that which occurs after the ingestion of large volumes of water. In the latter case, the urine is primarily made up of water, and solute excretion is not increased.

• In contrast, diuretics result in the enhanced excretion of both solute and water. All diuretics (except aquaretics, which will be discussed) have as their common mode of action the primary inhibition of Na⁺ reabsorption by the nephron.
• Consequently, they cause an increase in the excretion of Na⁺, termed natriuresis. However, the effects of diuretics are not limited to Na⁺ handling.
• The renal handling of many other solutes also is influenced, usually as a consequence of alterations in Na⁺ transport. Recently, drugs have been developed that block the action of arginine vasopressin (AVP) on the distal tubule and collecting duct.
• These drugs, called aquaretics, cause water diuresis. This chapter reviews the cellular mechanisms of action of various diuretics and the nephron sites at which these diuretics act.

In addition to their effects on Na+ handling by the nephron, their effects on the renal handling of other solutes

“Understanding how diuretics work in the body”

Example:

K⁺, Ca⁺⁺, inorganic phosphate [P_i], and bicarbonate [HCO₃^–]) and of water are considered. The effects of aquaretics on water excretion also are discussed.

General Principles Of Diuretic Action

“How do diuretics affect kidney function?”

The primary action of diuretics is to increase the excretion of Na⁺.

• Alterations in Na⁺ excretion by the kidneys result in alterations in the volume of the extracellular fluid (ECF) compartment. Consequently, diuretics decrease the volume ofthe ECF.
• Indeed, diuretics commonly are given in clinical situations when the ECF compartment is expanded, with the intent of reducing its volume.
• Because the ECF volume also determines blood volume and pressure, diuretics commonly are used in the therapy of hypertension.
• Although generally predictable for a particular class of diuretics, the effects of diuretic administration can be quite variable.

Several factors are important in determining the overall effect of a particular diuretic:

• The nephron segment where the diuretic acts
• The response of nephron segments not directly affected by the diuretic
• The delivery of sufficient quantities of the diuretic to its site of action
• The volume of the ECF

“Importance of studying diuretic action in medicine”

Sites of Action of Diuretics

Depicts the nephron sites at which the different classes of diuretics act. The osmotic diuretics act along the proximal tubule and portions of the thin descending limb of Henle’s loop (i.e., those portions of the nephron that have a high water permeability).

• The early portion of the distal tubule is the site of action of the thiazide diuretics, and the K⁺– sparing diuretics act primarily on the late portion of the distal tubule and theoretical portion of the collecting duct where they not only inhibit Na⁺ reabsorption but also K⁺ secretion.
• This same class of diuretics also can inhibit Na⁺ reabsorption in portions of the collecting duct that do not secrete K⁺.
• The site of action of a diuretic in turn determines the magnitude of the associated natriuresis.
• For example, diuretics acting on the thick ascending limb of Henle’s loop cause a larger diuresis than diuretics acting on the early portion of the distal tubule, because a larger portion of the filtered Na⁺ is absorbed by the thick ascending limb.

The effect diuretics have on the handling of solutes other than Na+ also depends on the site of action. Examples illustrating this point are given in subsequent sections.

“Common types of diuretics explained”

“Role of loop diuretics in renal physiology”

Response of Other Nephron Segments

When a diuretic inhibits Na⁺ reabsorption at one nephron site, it causes increased delivery of Na⁺ and water to more distal segments. The function of these more distal segments and their ability or inability to handle this increased load ultimately determine the overall effect of the diuretic on urinary solute and water excretion.

Examples of this phenomenon are considered in detail with a discussion of each of the various diuretics. In addition, diuretic-induced changes in ECF volume (discussed later in this chapter) may modulate Na⁺ transport in segments of the nephron not directly affected by the diuretic and thereby influence the degree of natriuresis.

“How thiazide diuretics reduce blood pressure”

Adequate Delivery of Diuretics to Their Site of Action

The effect of a diuretic on Na⁺ excretion also depends on the delivery of adequate quantities of the drug to its site of action. Except for the aldosterone antagonists, which act intracellularly, diuretics act from the lumen of the nephron (carbonic anhydrase inhibitors have both luminal and intracellular sites of action).

Diuretics gain access to the lumen by glomerular filtration and through secretion by the organic anion and organic cation secretory systems located in the proximal tubule

Because some diuretics are bound to plasma proteins

Example: Loop diuretics

Loop diuretics secretion by the proximal tubule is the primary mechanism for the delivery of the diuretic to its site of action in the lumen of the nephron. Thus the effect of a diuretic can be blunted if, for example, it is administered with another drug that competes for the same organic anion and organic cation secretory mechanism.

The volume of the Extracellular Fluid

The effect of a diuretic also depends on the volume of the ECF.

• When the volume of the ECF is decreased, the glomerular filtration rate (GFR) is reduced, thereby reducing the amount of filtered Na⁺.
• In addition, Na+ reabsorption by the nephron is enhanced.
• Thus the effect of a diuretic that acts on the distal tubule would be blunted if administered in the setting of a reduced ECF volume.

Under this condition, the decreased GFR (i.e., decreased filtered Na⁺), together with enhanced Na⁺reabsorption by the proximal tubule, would result in the delivery of a smaller quantity of Na⁺ to the distal tubule. Thus even if the diuretic completely inhibited Na⁺ reabsorption in the distal tubule, the associated natriuresis would be less than would occur if the ECF volume were normal.

“Mechanism of potassium-sparing diuretics explained”

Diuretic Braking Phenomenon

As illustrated, administration of a diuretic to a person with fied Na+ intake results in a short-lived natriuresis.

• The transient response, called the diuretic braking phenomenon, reflects several changes in renal function that are both a direct effect of the diuretic and secondary to changes in the volume of the ECF.
• One component of this response is that diuretic-induced inhibition of Na⁺ reabsorption in the targeted nephron segment increases Na⁺ delivery to more distal nephron segments and simulates Na⁺ reabsorption at these sites.
• A second important component of this response is that the loss of sodium chloride (NaCl) and water from the body as a result of diuretic action decreases the volume of the ECF. This decrease in turn is sensed by the body’s vascular baroreceptors and effector mechanisms, prompting them to increase NaCl and water conservation by the kidneys

“Impact of carbonic anhydrase inhibitors on diuresis”

Studies in experimental animals have shown that loop and thiazide diuretics increase the expression of the transporters they inhibit.

For example, loop diuretics, which inhibit the Na⁺-K⁺-2Cl^– cotransporter (NKCC2) in the apical membrane of the cells of the thick ascending limb of Henle’s loop, also increase the expression of the transporter in this segment.

• Similarly, thiazide diuretics, which inhibit the Na⁺-Cl^– − symporter (NCC) in the apical membrane of the early portion of the distal tubule, also increase the expression of these transporters in this segment.
• In addition, both loop and thiazide diuretics increase the expression of the Na⁺ channel (epithelial sodium channel [ENaC]) in the late portion of the distal tubule and collecting duct.
• Thiazide diuretics also increase the expression of aquaporin-2 in the principal cells of the late portion of the distal tubule and the collecting duct. Whether this effect is direct or indirect (i.e., related to changes in ECF volume) is uncertain.
• Regardless of the mechanism, the increased expression of aquaporin-2 is expected to increase water reabsorption by the arginine vasopressin (AVP)- sensitive nephron segments.
• With the diuretic-induced decrease in the ECF volume, the renin-angiotensin in-aldosterone system is activated, renal sympathetic nerve activity is increased, and
• AVP secretion is stimulated, which in combination acts to reduce urinary sodium chloride (NaCl) and water excretion.
• At the cellular level, angiotensin II increases the expression of the Na⁺-Cl^– symporter in the early portion of the distal tubule, and aldosterone increases the expression of ENaC in the late distal tubule and collecting duct.
• AVP also increases the expression of key transporters. Specifically, AVP increases the expression of NKCC2 in the thick ascending limb of Henle’s loop, NCC in the early portion of the distal tubule, and ENaC in the late distal tubule and collecting duct.

Finally, angiotensin II increases the abundance of the Na⁺-H⁺ antiporter (NHE3) in the proximal tubule. Upregulation of these transporters by diuretics reduces their efficacy, and when the diuretic administration is terminated, results in a rapid increase in NaCl reabsorption.

“Osmotic diuretics: Uses and mechanism of action”

• As a result of the braking phenomenon, a new steady state is reached where even with continued administration of the diuretic, urinary Na+ excretion once again equals intake.
• However, this steady state occurs at a reduced ECF volume, which is detected as a decrease in body weight. When diuretic therapy is discontinued, renal Na+ excretion is reduced.
• After a period of positive Na⁺ balance, during which the ECF returns to normal (i.e., return of body weight to its original value), a new steady state is again achieved.
• The concept of a steady state deserves special emphasis. Normally, persons are in a steady-state balance between solute (Example: Na⁺) and water, with intake equaling excretion.
• Administration of a diuretic temporarily disrupts this balance by increasing solute and water excretion, and a negative balance exists. However, solute and water excretion cannot exceed intake indefinitely, and a new steady state eventually is achieved.
• In this new steady state, intake, and excretion are again balanced, but the ECF volume is reduced as a result of the diuretic-induced excretion of NaCl and water.
• In general, when a person has been taking a diuretic for several days or longer, a new steady state is achieved.
• If Na⁺ intake is not increased, the ECF volume is decreased in proportion to the degree of negative Na+ balance.

Mechanisms of action of diuretics

1. Osmotic Diuretics

Osmotic diuretics, as the name implies, are agents that inhibit the reabsorption of solute and water by altering osmotic driving forces along the nephron.

• Unlike the other classes of diuretics, osmotic diuretics do not inhibit a specific membrane transport protein; they simply affect water transport across the cells of the nephron through the generation of an osmotic pressure gradient.
• The best example of an exogenous osmotic diuretic is the sugar mannitol.
• When present in abnormally high concentrations, freely filtered endogenous substances such as glucose (i.e., in patients with diabetes mellitus) and urea (i.e., in patients with renal disease whose plasma urea levels are elevated) also can act as osmotic diuretics.
• Osmotic diuretics (For example:, mannitol) gain access to the proximal tubular fluid by glomerular filtration.
• Because they are not reabsorbed or are only poorly reabsorbed, they remain within the tubular lumen, where they can exert an osmotic pressure that inhibits tubular fluid reabsorption.
• Osmotic diuretics affect fluid reabsorption in the segments that have high permeability to water (i.e., the proximal tubule and portions of the thin descending limb of Henle’s loop).
• Because of the large volumes of filtrate reabsorbed in the proximal tubule (60% to 70% of the filtrate), this nephron site is most important when considering the action of osmotic diuretics.

“How do diuretics influence the nephron?”

The reabsorption of the tubular flid by the proximal tubule is essentially an isosmotic process (i.e., the osmolality of the reabsorbed fluid is only slightly hyperosmotic compared with that of the tubular flid).

• Solute (primarily NaCl) is actively reabsorbed by the proximal tubule cells.
• This reabsorption sets up a small osmotic pressure difference across the tubule, with the tubular fluid being 3 to 5 mOsm/kg H₂O hypoosmotic concerning the interstitial fluid.
• Given the fact that water is readily able to cross the proximal tubule, this small osmotic pressure gradient is sufficient to cause water reabsorption.
• Also, as water flows from the lumen to the interstitium, it brings additional solute with it by solvent drag.
• When an osmotic diuretic is present in the tubular flid, its concentration increases progressively as a result of NaCl and water reabsorption by the nephron. With this increase in concentration, an osmotic gradient develops opposite to the normal gradient generated by NaCl reabsorption.
• As a result, both NaCl (solvent drag component) and water reabsorption are reduced. With osmotic diuresis, an increase in blood flow to the medulla of the kidney also occurs.
• This increase in blood flw dissipates the standing interstitial osmotic gradient and thus also impairs water reabsorption by the descending limb of Henle’s loop and the medullary collecting duct.
• Some of the Na⁺ that is not reabsorbed by the proximal tubule is reabsorbed downstream by the thick ascending limb, distal tubule, and collecting duct.
• Thus the degree of natriuresis seen with osmotic diuretics is less than expected based on the magnitude of proximal tubule reabsorption.

Although Na⁺ excretion rates are as high as 60% of the filtered Na⁺ have been seen in experimental situations, the usual natriuresis seen in persons treated with osmotic diuretics is only about 10% of the filtered Na⁺.

“Role of the loop of Henle in diuretic action”

2. Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors

Example: Acetazolamide) reduce Na⁺ reabsorption by their effect on carbonic anhydrase.

This enzyme is abundant in the proximal tubule and therefore represents the major site of action of these diuretics. Carbonic anhydrase also is present in other cells along the nephron

Example:

Thick ascending limb of Henle’s loop and intercalated cells of the collecting duct), and administration of carbonic anhydrase inhibitors affect the activity of the enzyme at these sites as well.

• However, the effects of these diuretics are almost entirely attributed to their inhibition of the enzyme in the proximal tubule.
• This phenomenon reflects the fact that approximately one-third of proximal tubule Na⁺ reabsorption occurs in exchange for H⁺ (through the Na⁺-H⁺ antiporter) and thus depends on the activity of carbonic anhydrase
• Even though one-third of proximal tubule Na⁺ reabsorption is coupled to the secretion of H⁺, inhibition of this process by the carbonic anhydrase inhibitors does not result in a large natriuresis for several reasons.
• First, even with complete inhibition of carbonic anhydrase, some Na⁺ reabsorption (linked to bicarbonate reabsorption) still occurs. Second, downstream nephron segments increase their reabsorption of Na⁺

“Impact of diuretics on glomerular filtration rate (GFR)”

Example:

The thick ascending limb, distal tubule, and collecting duct), and third, increased delivery of Na⁺ to the macula densa leads to a reduction in the GFR by the tubuloglomerular feedback mechanism.

• Finally, with long-term administration, metabolic acidosis develops, which further decreases the effect of carbonic anhydrase inhibitors by reducing the filtration of HCO₃^– (i.e., the percentage of Na⁺reabsorbed with HCO₃^– in the proximal tubule is reduced).
• Typically, administration of carbonic anhydrase inhibitors results in Na⁺ excretion rates that are 5% to 10% of the filtered Na⁺.

3.  Loop Diuretics

Loop diuretics

Example:

Furosemide, bumetanide, torsemide, and ethacrynic acid) are organic anions that enter the tubular lumen primarily through secretion by the organic anion secretory system of the proximal tubule.

• They directly inhibit Na+ reabsorption by the thick ascending limb of Henle’s loop by blocking the Na⁺-K⁺-2Cl^– symporter located in the apical membrane of these cells.
• By this action, they not only inhibit Na⁺ reabsorption but also disrupt the ability of the kidneys to dilute and concentrate the urine. Dilution is impaired because the solute
• (NaCl) reabsorption by the water-impermeable thick ascending limb of Henle’s loop is inhibited.
• NaCl reabsorption by the medullary portion of the thick ascending limb also is critical for the generation and maintenance of an elevated medullary interstitial fluid osmolality.
• Therefore inhibition of NaCl transport by loop diuretics results in a decrease in the osmolality of the medullary interstitial fluid.
• With a decrease in medullary interstitial fluid osmolality, water reabsorption from the collecting duct is impaired, and the concentrating ability of the kidneys is reduced. Water reabsorption from some portions of the thin descending limb of
• Henle’s loop also is impaired by loop diuretics, again because of the decrease in medullary interstitial fluid osmolality.
• This decrease in thin descending limb water reabsorption accounts in part for the increase in water excretion seen with loop diuretics.

“How does diuretic action affect tubular reabsorption?”

Loop diuretics are the most potent diuretics available, increasing the excretion of Na⁺ to as much as 25% of the amount filtered. This large natriuresis reflcts the fact that the thick ascending limb normally reabsorbs approximately 20% to 25% of the filtered Na⁺ and that downstream segments of the nephron have a limited ability to reabsorb the excess Na⁺ delivered as a consequence of loop diuretic action

4. Thiazide Diuretics

Like the loop diuretics, thiazide diuretics (Example: Hydrochlorothiazide, chlorthalidone, and metolazone)* are organic anions.

• Because they largely are bound to plasma proteins, they gain access to the tubular lumen primarily by secretion in the proximal tubule.
• They act to inhibit Na⁺ reabsorption in the early portion of the distal tubule by blocking the Na⁺-Cl^– symporter in the apical membrane of these cells.
• Because water cannot cross this portion of the nephron, it is a site where the urine is diluted. Therefore thiazides reduce the ability to dilute the urine maximally by inhibiting NaCl reabsorption.
• Because thiazide diuretics act in the cortex and not the medulla, they do not affect the ability of the kidneys to concentrate the urine maximally. Natriuresis with thiazide diuretics is 5% to 10% of the fitered Na⁺

5. K⁺-Sparing Diuretics

K⁺-sparing diuretics act on the region of the nephron where K+ secretion occurs (i.e., the late portion of the distal tubule and cortical collecting duct). They produce a small natriuresis (3% to 5% of the filtered Na⁺), reflecting the amount of Na⁺ reabsorbed by this region of the nephron. As the name implies, their utility lies in their ability to inhibit K⁺ secretion by this region of the nephron.

“Diuretics and their role in regulating urine production”

There are two classes of K⁺ – sparing diuretics:

• One acts by antagonizing the action of aldosterone on the principal cell
• Example: Spironolactone and eplerenone), whereas the other class blocks the entry of
• Na⁺ into the same cells through the Na⁺– selective channels (epithelial sodium channels [ENaC]) in the apical membrane

Example:

Amiloride and triamterene). Amiloride and triamterene are organic cations that enter the tubular lumen primarily by secretion by the organic cation secretory system of the proximal tubule.

• Aldosterone stimulates both Na⁺ reabsorption and K⁺ secretion by the principal cells of the late distal tubule and collecting duct.
• Thus in the presence of an aldosterone antagonist, these effects are inhibited and both Na⁺ reabsorption and K⁺ secretion are reduced.
• The ability of the Na⁺ channel blockers amiloride and triamterene to inhibit Na⁺ reabsorption and K⁺ secretion is similar to that of spironolactone, but the cellular mechanism is different.

Amiloride and triamterene block the entry of Na⁺ into the principal cell by directly inhibiting the Na⁺ channel (ENaC) in the apical membrane.

• With decreased Na⁺ entry, reduced Na⁺ extrusion occurs across the basolateral membrane through Na⁺– K⁺ –adenosine triphosphatase (ATPase).
• This effect in turn reduces cellular K⁺ uptake and ultimately its secretion into the tubular fluid. Inhibition of apical membrane Na⁺ channels also alters the electrical profile across the luminal membrane, with the voltage across this membrane increasing in magnitude.
• Because of this voltage change, the electrochemical gradient for K⁺ movement out of the cell is reduced

This membrane voltage effect also contributes to the inhibition of K+ secretion. Trimethoprim is an antibiotic used to treat Pneumocystis jerovecii infections. P. jerovecii infections are commonly seen in persons whose immune systems are compromised

Example:  Persons with acquired immunodeficiency syndrome).

Hyperkalemia may occur in persons treated with trimethoprim as a result of reduced renal K⁺ excretion. K⁺ excretion is reduced because trimethoprim inhibits K⁺ secretion by the principal cells of the late distal tubule and cortical collecting duct. The mechanism for this inhibition of K⁺ secretion is similar to that of amiloride and triamterene (i.e., direct inhibition of the Na⁺ channel [ENaC] in the apical membrane of the cell)

6. Aquaretics

In recent years, drugs that are antagonists of the AVP receptor (V2) have been developed

Example:

Tolvaptan and lixivaptan. These drugs act on the late portion of the distal tubule and the collecting duct to block the action of AVP.

• As a result of their action, the urine cannot be concentrated and dilute urine is excreted, reflecting the fact that tubular fluid reaching these AVP-sensitive segments of the nephron is hypoosmotic to the ECF
• These drugs are particularly helpful in treating patients whose ECF is hypoosmotic as a result of the failure of the kidneys to excrete solute-free water because AVP levels are elevated by nonosmotic and nonhemodynamic mechanisms

“Pathophysiology of diuretic-induced electrolyte imbalances”

Example: Syndrome of inappropriate AVP secretion [SIADH] *

Effect Of Diuretics On The Excretion Of Water And Solutes

Through their effects on Na⁺ handling along the nephron, diuretics also influence the handling of water and solutes. The various diuretics on the handling of some of these solutes and the ability of the kidneys to excrete (CH₂O) and reabsorb (TCH₂O) solute-free water.

1. Solute-Free Water

The ability of the kidneys to excrete or reabsorb solute-free water depends on several factors.

About the action of diuretic agents, the factors of concern are as follows: 

• The normal function of the nephron segments (particularly the thick ascending limb)
• The delivery of adequate solute to Henle’s loop
• The maintenance of a hyperosmotic medullary interstitium (selective reabsorption of solute-free water)

The thick ascending limb of Henle’s loop is the most important site for the separation of solute and water.

• As noted, this separation not only dilutes the tubular fluid but also, by establishing a hyperosmotic medullary interstitium, allows water reabsorption from the collecting duct and thus the concentration of the urine.
• Inhibition of thick ascending limb Na⁺ reabsorption by loop diuretics therefore results in inhibition of both solute-free water excretion (CH₂O) and solute-free water reabsorption (TCH₂O).
• The early portion of the distal tubule is also a site of solute and water separation and thus tubular fluid dilution. Accordingly, inhibition of Na+ reabsorption by the thiazide diuretics impairs dilution of the urine.
• However, thiazide diuretics impair urine dilution to a lesser degree than do loop diuretics, reflecting the difference in the NaCl reabsorptive capacity between the distal tubule (5% of the filtered Na⁺) and the thick ascending limb (25% of the filtered Na⁺).
• In contrast to loop diuretics, thiazide diuretics do not significantly impair the ability of the kidneys to concentrate the urine.
• As already noted, the concentration of the urine requires a hyperosmotic medullary interstitium so that water can be reabsorbed from the collecting duct in the presence of AVP.
• Because thiazide diuretics act on distal tubules that are located in the cortex, their action at this site does not appreciably alter the medullary interstitial osmotic gradient.
• Consequently, urine-concentrating ability is unaffected by thiazide diuretics.
• The action of diuretics in the proximal tubule (osmotic diuretics and carbonic anhydrase inhibitors) increases the delivery of NaCl and water to Henle’s loop.

“Emerging research on diuretic mechanisms”

Because of the ability of the thick ascending limb to increase its transport rate in response to an increased delivered load of NaCl, the separation of solute and water increases. As a result, these diuretic agents increase the ability of the kidneys to excrete solute-free water and reabsorb solute-free water.

• Thus diuretics that act on the proximal tubule enhance the ability to concentrate and dilute the urine.
• Although the late portion of the distal tubule and the collecting duct can dilute the luminal fluid in the absence of AVP, Na⁺ transport in these segments is not of sufficient magnitude to contribute significantly to the excretion of solute-free water. Consequently, the K⁺-sparing diuretics do not appreciably alter free-water excretion.
• Like thiazide diuretics, K+-sparing diuretics do not alter solute-free water reabsorption because the nephron sites of action are located in the cortex.
• Aquaretics, because they act directly on the medullary portion of the collecting duct, increase solute-free water excretion and impair solute-free water reabsorption.
• K⁺ Excretion One of the major consequences of diuretic use (excluding the K⁺-sparing diuretics) is increased excretion of K⁺, which can be of sufficient magnitude to result in hypokalemia. The basis for this diuretic-induced increase in renal K⁺ excretion lies in the fact that when a diuretic inhibits Na⁺ and water reabsorption in segments upstream from the late portion of the distal tubule and cortical collecting duct (K⁺secretory site of the nephron), tubular fluid flow rate increases.
• The increased tubular fluid flow rate stimulates K⁺ secretion at this site addition, by their action on Na⁺ balance, diuretics decrease the ECF volume. This mechanism, in turn, leads to increased secretion of aldosterone by the adrenal cortex, which acts at this site to stimulate K⁺ secretion.
• The decrease in ECF volume also stimulates AVP secretion. As described, AVP stimulates K⁺ secretion by the principal cells of the late distal tubule and collecting duct.
• This stimulatory effect normally is offset by the inhibitory effect of the reduced tubular flow rate, which also is induced by AVP.
• As a result, AVP does not normally alter renal K⁺ excretion. However, in the presence of a diuretic that is acting upstream to the late portion of the distal tubule and the collecting duct, AVP does increase renal K⁺ excretion because in this setting tubular fluid flow is elevated by the action of the diuretics.
• Because K+-sparing diuretics prevent the increase in K⁺ excretion caused by the other diuretics, they usually are given in combination with these other diuretics to prevent or at least minimize the development of hypokalemia.

“Case studies on diuretic therapy outcomes”

2. HCO₃^– Excretion

By inhibiting H⁺ secretion in the proximal tubule and thereby increasing HCO₃^– excretion, carbonic anhydrase inhibitors can result in the development of metabolic acidosis.

• Although only carbonic anhydrase inhibitors directly alter H⁺ secretion by the nephron, all diuretics can affect systemic acid-base balance secondarily.
• Both loop and thiazide diuretics can induce metabolic alkalosis, which is a consequence of the decrease in ECF volume that accompanies their use. With a decrease in the ECF volume, Na⁺ is more avidly reabsorbed by the nephron.
• In the proximal tubule, this enhanced Na+ reabsorption results in enhanced H⁺ secretion through the Na⁺-H⁺ antiporter.
• Thus a greater fraction of the fitered HCO₃^– is reabsorbed. In addition, the reduction in ECF volume stimulates aldosterone secretion by the adrenal cortex. Aldosterone stimulates H⁺ secretion by intercalating cells of the distal tubule and collecting duct.
• Because, as noted, proximal tubule HCO₃^– reabsorption is increased, virtually none of the filtered HCO₃^– reaches the distal tubule.

Therefore the increased H⁺ secretion that occurs in the distal tubule and collecting duct results in the production of new HCO₃^–  as the H⁺ is excreted with non HCO₃^– urinary buffers (i.e., titratable acid).

• The increased secretion of H⁺ in the distal tubule and collecting duct also enhances the excretion of NH₄⁺, which results in the addition of new HCO₃^– to the ECF. As a result, net acid excretion by the kidneys is increased and metabolic alkalosis develops.
• By inhibiting Na⁺ reabsorption in the late portion of the distal tubule and cortical collecting duct, K⁺ – sparing diuretics secondarily inhibit H⁺ secretion and thus can lead to the development of metabolic acidosis.
• H⁺secretion by these nephron segments is facilitated by the lumen-negative transepithelial voltage.
• Normally, Na⁺ reabsorption in these nephron segments results in the generation of such a voltage. By inhibiting Na⁺ reabsorption and thus the negative luminal voltage, K⁺ -sparing diuretics reduce H⁺secretion.
• With reduced H⁺  secretion, insufficient quantities of net acid are excreted and metabolic acidosis ensues.

“Complications of ignoring diuretic side effects”

3. Ca⁺⁺ and Pi Excretion 

With the Excretion of K⁺ – sparing diuretics, all the diuretics can significantly alter Ca⁺⁺ excretion by the kidney.

• With inhibition of proximal tubule solute and water reabsorption (osmotic diuretics and carbonic anhydrase inhibitors), reduced reabsorption of Ca⁺⁺ and thus increased excretion occurs.
• The amount of Ca⁺⁺ excreted is less than expected from inhibition of proximal tubule transport. This situation again reflects the ability of the downstream segments (particularly the thick ascending limb of Henle’s loop) to increase reabsorption after an increased delivery of Ca⁺⁺.
• The mechanism by which these diuretics inhibit proximal tubule Ca⁺⁺ reabsorption is related to their ability to reduce solvent drag. With the use of carbonic anhydrase inhibitors, increased Ca⁺⁺ excretion occurs in the setting of alkaline urine (increased urinary (HCO₃^– ).

Because Ca⁺⁺ is less soluble in alkaline urine, the potential exists for the formation of renal stones that contain Ca⁺⁺  Loop diuretics also increase Ca⁺⁺ excretion, an action explained by the effect of these diuretics on the transepithelial voltage of the thick ascending limb of Henle’s loop.

• Normally, the transepithelial voltage of this segment is oriented lumen positive 4), providing a driving force for the movement of Ca⁺⁺ from the lumen to blood through the paracellular pathway.
• When the transport of NaCl by Henle’s loop is blocked by loop diuretics, this lumen-positive voltage is abolished, and thus the driving force for Ca⁺⁺ reabsorption is reduced.
• Normally, Henle’s loop reabsorbs about 15% of the fitered Ca⁺⁺ Inhibition of Ca⁺⁺ reabsorption by loop diuretics therefore can have a significant effect on Ca⁺⁺ excretion.
• For this reason, loop diuretics often are used to treat hypercalcemia.
• Despite this action of loop diuretics, hypercalcemia can occur with their long-term use. The mechanism responsible for this effect is related to the diuretic-induced decrease in the ECF volume.
• When the ECF volume is decreased, proximal tubule reabsorption is enhanced, which increases Ca⁺⁺ reabsorption at this site and therefore decreases urinary Ca⁺⁺ excretion.

“Advances in understanding diuretic action”

Thiazide diuretics stimulate Ca⁺⁺ reabsorption by the cells of the distal tubule and thus reduce Ca⁺⁺ excretion. The distal tubule normally reabsorbs approximately 10% to 15% of the filtered Ca⁺⁺

• The reabsorption of Ca⁺⁺ at this site is an active, transcellular process involving the entry of Ca⁺⁺ into the cell through channels in the apical membrane and extrusion from the cell across the basolateral membrane by the Ca⁺⁺ -ATPase and 3Na ⁺– Ca⁺⁺ antiporter.
• Thiazide diuretics, by inhibiting the entry of NaCl into the cell, cause the membrane potential to hyperpolarize (i.e., the cell interior becomes more electrically negative).
• This hyperpolarization in turn activates the Ca⁺⁺ channel (TRPV5) in the apical membrane of the cell and increases the electrochemical gradient for Ca⁺⁺ entry into the cell.
• The increased entry of Ca⁺⁺ into the cell is matched by increased extrusion across the basolateral membrane by the Ca⁺⁺-ATPase and 3Na⁺– Ca⁺⁺antiporter (extrusion of Ca⁺⁺ via the 3Na⁺– Ca⁺⁺ antiporter is stimulated because the intracellular concentration of Na⁺ is decreased as a result of the diuretic blocking NaCa⁺ entry into the cell across the apical membrane).
• The net effect is an increase in Ca⁺⁺ reabsorption.

“Global prevalence of diuretic use in hypertension”

• With long-term use of thiazide diuretics, the associated decrease in ECF volume stimulates proximal tubule reabsorption, including that of Ca⁺⁺
• Because thiazides reduce urinary Ca⁺⁺ excretion, they sometimes are used to lower the incidence of the formation of stones containing Ca⁺⁺ in persons who normally excrete high levels of Ca⁺⁺ in their urine. Except for the K⁺-sparing diuretics, all diuretics acutely increase Pi excretion.
• However, the cellular mechanisms for this effect are not completely understood.

The effect is modifid, however, with long-term diuretic therapy. With the decrease in ECF volume that accompanies long-term diuretic use, proximal tubule Na⁺  reabsorption is stimulated. Because the proximal tubule reabsorbs the largest portion of the filtered Pi and because this reabsorptive process is coupled with Na⁺, P_i excretion is reduced in this setting.

The post Physiology Of Diuretic Action appeared first on BDS Notes.

“What is the regulation of potassium balance?”

Potassium, which is one of the most abundant cations in the body, is critical for many cell functions, including cell volume regulation, intracellular pH regulation, DNA and protein synthesis, growth, enzyme function, resting membrane potential, and cardiac and neuromuscular activity. Despite wide fluctuations in dietary K⁺ intake, [K⁺] in cells and extracellular fluid (ECF) remains remarkably constant. Two sets of regulatory mechanisms safeguard K⁺ homeostasis. First, several mechanisms regulate the [K⁺] in the ECF. Second, other mechanisms maintain the amount of K⁺ in the body constant by adjusting renal K+ excretion to match dietary K+ intake. The kidneys regulate K⁺ excretion.

Overview Of K⁺ Homeostasis

Total body K⁺ is 50 mEq/kg of body weight or 3500 mEq for a person weighing 70 kg. A total of 98% of the K⁺ in the body is located within cells, where its average [K+] is 150 mEq/L. A high intracellular [K⁺] is required for many cell functions, including cell growth and division and volume regulation. Only 2% of the total body K+ is located in the ECF, where its normal concentration is approximately 4 mEq/L. [K⁺] in the ECF that exceeds 5.0 mEq/L constitutes hyperkalemia. Conversely, [K⁺] in the ECF of less than 3.5 mEq/L constitutes hypokalemia. Hypokalemia is one of the most common electrolyte disorders in clinical practice and can be observed as

“Understanding potassium homeostasis in the body”

“How is potassium balance regulated in the human body?”

The effects of variations in plasma K⁺ concentration on the resting membrane potential of skeletal muscle. Hyperkalemia causes the membrane potential to become less negative and decreases the excitability by inactivating fast Na+ channels, which are responsible for the depolarizing phase of the action potential.

• Hypokalemia hyperpolarizes the membrane potential and thereby reduces excitability because a larger stimulus is required to depolarize the membrane potential to the threshold potential. Resting indicates the “normal” resting membrane potential. Normal threshold indicates the membrane threshold potential.
• As many as 20% of hospitalized patients. The most common causes of hypokalemia include administration of diuretic drugs (see Chapter 10), surreptitious vomiting (i.e., bulimia), and severe diarrhea. Gitelman syndrome (a genetic defect in the Na+-Cl− symporter in the apical membrane of distal tubule cells) also causes hypokalemia (see Chapter 4, Table 4-3).
• Hyperkalemia also is a common electrolyte disorder and is seen in 1% to 10% of hospitalized patients.
• Hyperkalemia often is seen in patients with renal failure, in persons taking drugs such as angiotensin-converting enzyme inhibitors and K⁺– sparing diuretics (see Chapter 10), in persons with hyperglycemia (i.e., high blood sugar), and the elderly. Pseudohyperkalemia, a falsely high plasma [K⁺], is caused by traumatic lysis of red blood cells while blood is being drawn.
• Red blood cells, like all cells, contain K⁺, and the lysis of red blood cells releases K⁺ into the plasma, artificially elevating the plasma [K⁺]. The large concentration difference of K+ across cell membranes (approximately 146 mEq/L) is maintained by the operation of sodium-potassium–adenosine triphosphatase (Na+-K+-ATPase). This K+ gradient is important in maintaining the potential difference across cell membranes.
• Thus K⁺ is critical for the excitability of nerve and muscle cells and for the contractility of cardiac, skeletal, and smooth muscle cells.
• Cardiac arrhythmias are produced by both hypokalemia and hyperkalemia. The electrocardiogram (ECG; monitors the electrical activity of the heart and is a quick and easy way to determine whether changes in plasma [K⁺] influence the heart and other excitable cells. In contrast, measurements of the plasma [K⁺] by the clinical laboratory require a blood sample, and values often are not immediately available.

“Importance of potassium balance for overall health”

The first sign of hyperkalemia is the appearance of tall, thin T waves on the ECG. Further increases in the plasma [K⁺] prolong the PR interval, depress the ST segment, and lengthen the QRS interval on the ECG. Finally, as the plasma [K⁺] approaches 10 mEq/L, the P wave disappears, the QRS interval broadens, the ECG appears as a sine wave, and the ventricles fibrillate (i.e., manifest rapid, uncoordinated contractions of muscle fibers). Hypokalemia prolongs the QT interval, inverts the T wave, and lowers the ST segment on the ECG.

“Common causes of potassium imbalance explained”

Electrocardiograms from persons with varying plasma K⁺ concentrations. Hyperkalemia increases the height of the T wave, and hypokalemia inverts the T wave. (Modified from Barker L, Burton J, Zieve P: Principles of ambulatory medicine, ed 5, Baltimore, 1999, Williams & Wilkins.)

After a meal, the K⁺ absorbed by the gastrointestinal tract enters the ECF within minutes (Figure 7-3). If the K⁺ ingested during a normal meal ( ≈33 mEq) were to remain in the ECF compartment (14 L), the plasma [K⁺] would increase by a potentially lethal 2.4 mEq/L (33 mEq added to 14 L of ECF):

33 mEq/14 L = 2.4 mEq/L (7-1)

This rise in the plasma [K⁺] is prevented by the rapid uptake (within minutes) of K⁺ into cells. Because the excretion of K+ by the kidneys after a meal is relatively slow (within hours), the uptake of K+ by cells is essential to prevent life-threatening hyperkalemia. Maintaining total body K+ constant requires all the K+ absorbed by the gastrointestinal tract to eventually be excreted by the kidneys. This process requires about 6 hours.

“Role of the kidneys in potassium regulation”

Regulation Of Plasma [K⁺]

As illustrated in Figure 7-3 and Box 7-1, several hormones, including epinephrine, insulin, and aldosterone, increase K⁺ uptake into skeletal muscle, liver, bone, and red blood cells by stimulating Na+-K+- ATPase, the Na+-K+-2Cl− symporter, and the Na+- Cl− symporter in these cells. Acute stimulation of K⁺ uptake (i.e., within minutes) is mediated by an increased turnover rate of existing Na+-K+-ATPase, Na+-K+-2Cl−, and Na+-Cl− transporters, whereas the chronic increase in K⁺ uptake (i.e., within hours to days) is mediated by an increase in the quantity of Na+-K⁺-ATPase. A rise in the plasma [K+] that follows K+ absorption by the gastrointestinal tract stimulates insulin secretion from the pancreas, aldosterone release from the adrenal cortex, and epinephrine secretion from the adrenal medulla.

“How aldosterone affects potassium balance”

Overview of potassium homeostasis. An increase in plasma insulin, β-adrenergic agonists, or aldosterone stimulates K⁺ movement into cells and decreases plasma K⁺ concentration ([K⁺]), whereas a decrease in the plasma concentration of these hormones moves K+ into cells and increases plasma [K⁺]. α-Adrenergic agonists have the opposite effect.

• The amount of K⁺ in the body is determined by the kidneys. A person is in K⁺ balance when dietary intake and urinary output (plus output by the gastrointestinal tract) are equal. The excretion of K+ by the kidneys is regulated by plasma [K⁺], aldosterone, and arginine vasopressin.
• In contrast, a decrease in the plasma [K⁺] inhibits the release of these hormones. Whereas insulin and epinephrine act within a few minutes, aldosterone requires about 1 hour to stimulate K⁺ uptake into cells.

Epinephrine

Catecholamines affect the distribution of K⁺ across cell membranes by activating α- and β2-adrenergic receptors. The stimulation of α-adrenoceptors releases K⁺ from cells, especially in the liver, whereas the stimulation of β2-adrenoceptors promotes K⁺ uptake by cells. For example, the activation of β²-adrenoceptors after exercise is important in preventing hyperkalemia. The rise in plasma [K⁺] after a K⁺-rich meal is greater if the patient has been pretreated with propranolol, a β²– adrenoceptor antagonist. Furthermore, the release of epinephrine during stress (e.g., myocardial ischemia) can lower the plasma [K⁺] rapidly.

“Impact of insulin on potassium homeostasis”

Insulin

Insulin also stimulates K⁺ uptake into cells. The importance of insulin is illustrated by two observations. First, the rise in plasma [K⁺] after a K⁺-rich meal is greater in patients with diabetes mellitus (i.e., insulin deficiency) than in healthy people. Second, insulin (and glucose to prevent insulin-induced hypoglycemia) can be infused to correct hyperkalemia. Insulin is the most important hormone that shifts K+ into cells after the ingestion of K⁺ in a meal.

Aldosterone

Aldosterone, like catecholamines and insulin, also promotes K⁺ uptake into cells. A rise in aldosterone levels (e.g., primary aldosteronism) causes hypokalemia, whereas a fall in aldosterone levels (e.g., in persons with Addison disease) causes hyperkalemia. As discussed later, aldosterone also stimulates urinary K⁺ excretion. Thus aldosterone alters the plasma [K+] by

Major Factors, Hormones, And Drugs Influencing The Distribution Of K⁺ Between The Intracellular And Extracellular Fluid Compartments

Physiologic: Keep Plasma [K⁺] Constant

• Adrenergic receptor agonists
• Insulin
• Aldosterone

Pathophysiologic: Displace Plasma [K⁺] From Normal

• Acid-base disorders
• Plasma osmolality
• Cell lysis
• Vigorous exercise

“Role of sodium-potassium pumps in potassium regulation”

Drugs That Induce Hyperkalemia

• Dietary potassium supplements
• Angiotensin-converting enzyme inhibitors
• K⁺-sparing diuretics (see Chapter 10)
• Heparin acts on K⁺ uptake into cells and by altering urinary
  K⁺ excretion.

Alterations Of Plasma [K⁺]

Several factors can alter the plasma [K⁺] (see Box 7-1). These factors are not involved in the regulation of the plasma [K⁺] but rather alter the movement of K⁺ between the intracellular fluid and ECF and thus cause the development of hypokalemia or hyperkalemia.

Acid-Base Balance

Metabolic acidosis increases the plasma [K⁺], whereas metabolic alkalosis decreases it. Respiratory alkalosis causes hypokalemia. Metabolic acidosis produced by the addition of inorganic acids (e.g., HCl and sulfuric acid) increases the plasma [K+] much more than an equivalent acidosis produced by the accumulation of organic acids (e.g., lactic acid, acetic acid, and keto acids).

• The reduced pH—that is, increased [H⁺]—promotes the movement of H+ into cells and the reciprocal movement of K⁺ out of cells to maintain electroneutrality.
• This effect of acidosis occurs in part because acidosis inhibits the transporters that accumulate K⁺ inside cells, including the Na+- K+-ATPase and the Na+-K+-2Cl− symporter. In addition, the movement of H+ into cells occurs as the cells buffer changes in the [H+] of the ECF. As H+ moves across the cell membranes, K⁺ moves in the opposite direction; thus cations are neither gained nor lost across cell membranes.
• Metabolic alkalosis has the opposite effect; the plasma [K⁺] decreases as K⁺ moves into cells and H⁺ exits. Although organic acids produce metabolic acidosis, they do not cause significant hyperkalemia. Two explanations have been suggested for the reduced ability of organic acids to cause hyperkalemia.
• First, the organic anion may enter the cell with H+ and thereby eliminate the need for K⁺/H⁺ exchange across the membrane. Second, organic anions may stimulate insulin secretion, which moves K⁺ into cells. This movement may counteract the direct effect of acidosis, which moves K⁺ out of cells.

“Biomechanics of potassium reabsorption and secretion”

Plasma Osmolality

The osmolality of the plasma also influences the distribution of K⁺ across cell membranes. An increase in the osmolality of the ECF enhances K⁺ release by cells and thus increases extracellular [K⁺]. The plasma [K⁺] may increase by 0.4 to 0.8 mEq/L for an elevation of 10 mOsm/kg H2O in plasma osmolality. In patients with diabetes mellitus who do not take insulin, plasma K⁺ often is elevated in part because of the lack of insulin and in part because of the increase in the concentration of glucose in plasma (i.e., from a normal value of ~100 mg/dL to as high as ~1200 mg/dL), which increases plasma osmolality. Hypoosmolality has the opposite action. The alterations in plasma [K⁺] associated with changes in osmolality are related to changes in cell volume. For example, as plasma osmolality increases, water leaves cells because of the osmotic gradient across the plasma membrane (see Chapter 1). Water leaves cells until the intracellular osmolality equals that of the ECF. This loss of water shrinks cells and causes the cell [K⁺] to rise. The rise in intracellular [K⁺] provides a driving force for the exit of K⁺ from cells. This sequence increases plasma [K⁺]. A fall in plasma osmolality has the opposite effect.

Cell Lysis

Cell lysis causes hyperkalemia, which results from the addition of intracellular K⁺ to the ECF. Severe trauma (e.g., burns) and some conditions such as tumor lysis syndrome (i.e., chemotherapy-induced destruction of tumor cells) and rhabdomyolysis (i.e., destruction of skeletal muscle) destroy cells and release K⁺ and other cell solutes into the ECF. In addition, gastric ulcers may cause the seepage of red blood cells into the gastrointestinal tract. The blood cells are digested, and the K⁺ released from the cells is absorbed and can cause hyperkalemia.

Exercise

During exercise, more K⁺ is released from skeletal muscle cells than during rest. The ensuing hyperkalemia depends on the degree of exercise. In people walking slowly, the plasma [K⁺] increases by 0.3 mEq/L. The plasma [K⁺] may increase by 2.0 mEq/L with vigorous exercise.

• Exercise-induced changes in the plasma [K⁺] usually do not produce symptoms and are reversed after several minutes of rest. However, vigorous exercise can lead to life-threatening hyperkalemia in persons
• who have endocrine disorders that affect the release of insulin, epinephrine (a β-adrenergic agonist), or aldosterone;
• whose ability to excrete K⁺ is impaired (e.g., because of renal failure); or
• who take certain medications, such as β2-adrenergic blockers. For example, during vigorous exercise, the plasma [K⁺] may increase by at least 2 to 4 mEq/L in persons who take β2-adrenergic receptor antagonists for hypertension.

“Mechanisms of potassium excretion by the kidneys”

Because acid-base balance, plasma osmolality, cell lysis, and exercise do not maintain the plasma [K⁺] at a normal value, they do not contribute to K⁺ homeostasis (see Box 7-1 ). The extent to which these pathophysiologic states alter the plasma [K⁺] depends on the integrity of the homeostatic mechanisms that regulate plasma [K⁺] (e.g., the secretion of epinephrine, insulin, and aldosterone).

K⁺ Excretion By The Kidneys

The kidneys play a major role in maintaining K⁺ balance. As illustrated in Figure 7-3, the kidneys excrete 90% to 95% of the K⁺ ingested in the diet. Excretion equals intake even when intake increases by as much as 10-fold.

• This balance of urinary excretion and dietary intake underscores the importance of the kidneys in maintaining K⁺ homeostasis. Although small amounts of K⁺ are lost each day in feces and sweat (approximately 5% to 10% of the K⁺ ingested in the diet), this amount is essentially constant (except during severe diarrhea), is not regulated, and therefore is relatively less important than the K⁺ excreted by the kidneys.
• K⁺ secretion from the blood into the tubular fluid by the cells of the distal tubule and collecting duct system is the key factor in determining urinary K⁺ excretion (Figure 7-4). Because K⁺ is not bound to plasma proteins, it is freely filtered by the glomerulus.
• When individuals ingest 100 mEq of K⁺ per day, urinary K⁺ excretion is about 15% of the amount filtered. Accordingly, K⁺ must be reabsorbed along the nephron. When dietary K⁺ intake increases, however, K⁺ excretion can, in extreme circumstances, exceed the amount filtered. Thus K⁺ also can be secreted.
• The proximal tubule reabsorbs about 67% of the filtered K⁺ under most conditions. Approximately 20% of the filtered K⁺ is reabsorbed by the loop of Henle, and, as with the proximal tubule, the amount reabsorbed is a constant fraction of the amount filtered.
• In contrast to these nephron segments, which can only reabsorb K⁺, the distal tubule and collecting duct can reabsorb or secrete K⁺.
• The rate of K+ reabsorption or secretion by the distal tubule and collecting duct depends on a variety of hormones and factors. When ingesting 100 mEq/day of K⁺ K⁺ is secreted by these nephron segments. A rise in dietary K⁺ intake increases K⁺ secretion. K⁺ secretion can increase the amount of K⁺ that appears in the urine so that it approaches 80% of the amount filtered

In contrast, a low-K⁺ diet activates K⁺ reabsorption along the distal tubule and collecting duct so that urinary excretion falls to about 1% of the K⁺ filtered by the glomerulus (see Figure 7-4). Because the kidneys cannot reduce K⁺ excretion to the same low levels as they can for Na+ (i.e., 0.2%), hypokalemia can develop

“Role of aldosterone in potassium excretion”

K⁺ Transport Along The Nephron. K⁺ Excretion Depends On The Rate And Direction Of K⁺ Transport By The Distal Tubule And Collecting Duct. Percentages Refer To The Amount Of Fitered K⁺ Reabsorbed Or Secreted By Each Nephron Segment. Left, Dietary K⁺ Depletion. An Amount Of K⁺ Equal To 1% Of The Fitered Load Of K⁺ Is Excreted. Right, Normal, And Increased Dietary K⁺ Intake. An Amount Of K⁺ Equal To 15% To 80% Of The Fitered Load Is Excreted.

“How does the renin-angiotensin-aldosterone system regulate potassium?”

• Ccd, Cortical Collecting Duct; Dt, Distal Tubule; Imcd, Inner Medullary Collecting Duct; Pt, Proximal Tubule; Tal, Thick Ascending Limb in persons who have a K⁺-deficient diet. Because the magnitude and direction of K⁺ transport by the distal tubule and collecting duct are variable, the overall rate of urinary K⁺ excretion is determined by these tubular segments.
• In persons with advanced renal disease, the kidneys are unable to eliminate K⁺ from the body, and thus the plasma [K⁺] rises.
• The resulting hyperkalemia reduces the resting membrane potential (i.e., the voltage becomes less negative), which decreases the excitability of neurons, cardiac cells, and muscle cells by inactivating fast Na⁺ channels, which are critical for the depolarization phase of the action potential.
• Severe, rapid increases in the plasma [K⁺] can lead to cardiac arrest and death. In contrast, in patients taking diuretic drugs for hypertension, urinary K⁺ excretion often exceeds dietary Kv intake. Accordingly, the K⁺ balance is negative, and hypokalemia develops.
• This decline in the extracellular [K⁺] hyperpolarizes the resting cell membrane (i.e., the voltage becomes more negative) and reduces the excitability of neurons, cardiac cells, and muscle cells.
• Severe hypokalemia can lead to paralysis, cardiac arrhythmias, and death. Hypokalemia also can impair the ability of the kidneys to concentrate the urine and can stimulate the renal production of ammonium, which affects acid-base balance.
• Therefore the maintenance of a high intracellular [K⁺], a low extracellular [K⁺], and a high K⁺ concentration gradient across cell membranes is essential for several cellular functions.

“Impact of antidiuretic hormone (ADH) on potassium balance”

Cellular Mechanism Of K⁺ Secretion By Principal Cells (A) And Α-Intercalated Cells (B) In The Distal Tubule And Collecting Duct.

• Α-Intercalated Cells Contain Very Low Levels Of Sodiumpotassium Adenosine Triphosphatase In The Basolateral Membrane (Not Shown).
• K⁺ Depletion Increases K⁺ Reabsorption By Α-Intercalated Cells By Stimulating H +-K+- Adenosine Triphosphatase (Hka). Ae1, Anion Exchanger 1; Atp, Adenosine Triphosphate; Bk, Ca++-Activated K+; Ca, Carbonic Anhydrase; Hco−3 , Bicarbonate; Kcc1, K+-Cl− Symporter 1; Romk, Renal Outer Medullary K+; V-Atpase, Vacuolar Adenosine Triphosphatase.

Cellular Mechanisms Of K⁺ Transport By Principal Cells And Intercalated Cells In The Distal Tubule And Collecting Duct

A illustrates the cellular mechanism of K⁺ secretion by principal cells in the distal tubule and collecting duct. Secretion from the blood into the tubule lumen is a two-step process: (1) K+ uptake from the blood across the basolateral membrane by Na+-K+- ATPase and (2) diffusion of K+ from the cell into the tubular fluid through K+ channels (the renal outer medullary K+ channel and the Ca++-activated K⁺ [BK] channel).

• A K+-Cl− symporter in the apical plasma membrane also secretes K⁺. Na+-K⁺-ATPase creates a high intracellular [K⁺], which provides the chemical driving force for K⁺exit across the apical membrane through K+ channels. Although K+ channels also are present in the basolateral membrane, K⁺ preferentially leaves the cell across the apical membrane and enters the tubular fluid. K+ transport follows this route for two reasons.
• First, the electrochemical gradient of K⁺ across the apical membrane favors its downhill movement into the tubular fluid. Second, the permeability of the apical membrane to K⁺ is greater than that of the basolateral membrane.
• Therefore K⁺ preferentially diffuses across the apical membrane into the tubular fluid. K⁺ secretion across the apical membrane via the K+-Cl− symporter is driven by the favorable concentration gradient of K⁺ between the cell and tubular fluid.
• The three major factors that control the rate of K⁺ secretion by the distal tubule and the collecting duct are:

1. The activity of Na+-K⁺+-ATPase
2. The driving force (electrochemical gradient for the K⁺ channel and the chemical concentration gradient for the K+-Cl− symporter) for K⁺ movement across the apical membrane
3. The permeability of the apical membrane to K⁺

“Steps in renal potassium handling explained”

Every change in K⁺ secretion by principal cells results from an alteration in one or more of these factors.

α-Intercalated cells reabsorb K⁺ by an H+-K+- ATPase transport mechanism located in the apical membrane (see Figure 7-5, B, and Chapter 4).

• This transporter mediates K⁺ uptake across the apical plasma membrane in exchange for H+. K⁺ exit from intercalated cells into the blood is mediated by a K⁺ channel.
• The reabsorption of K⁺ is activated by a low K⁺ diet. Intercalated cells also express the Ca++- activated, BK channels in the apical plasma membrane.
• K⁺ secretion by BK channels in intercalated cells (most likely α-intercalated cells) is activated by increased tubule flow rate, which enhances Ca++ uptake across the apical plasma membrane by activating a transient receptor potential channel also located in the apical plasma membrane (not shown in Figure 7-5, B).
• Increased intracellular Ca++ stimulates protein kinase C, which activates BK channels.

Regulation Of K⁺ Secretion By The Distal Tubule And Collecting Duct

The regulation of K⁺ excretion is achieved mainly by alterations in K⁺ secretion by principal cells of the distal tubule and collecting duct. Plasma [K⁺] and aldosterone are the major physiologic regulators of K⁺ secretion. Ingestion of a K⁺-rich meal also activates renal K⁺ excretion by a mechanism involving an unknown gut-dependent mechanism. Arginine vasopressin (AVP) also stimulates K⁺secretion; however, it is less important than the plasma [K⁺] and aldosterone.

Major Factors And Hormones Influencing K⁺ Excretion

Physiologic: Keep K⁺ Balance Constant

1. Plasma [K⁺]
2. Aldosterone
3. Arginine vasopressin

Pathophysiologic: Displace K⁺ Balance

1. The flow rate of tubule fluid
2. Acid-base disorders
3. Glucocorticoids

Other factors, including the flow rate of tubular fluid and acid-base balance, influence K⁺ secretion by the distal tubule and collecting duct. However, they are not homeostatic mechanisms because they disturb the K⁺ balance (Box 7-2).

“Causes and effects of hypokalemia (low potassium)”

Plasma [K⁺]

Plasma [K⁺] is an important determinant of K⁺ secretion by the distal tubule and collecting duct. Hyperkalemia (e.g., resulting from a high-K+ diet or from rhabdomyolysis) stimulates K⁺ secretion within minutes. Several mechanisms are involved.

• First, hyperkalemia stimulates Na+-K+- ATPase and thereby increases K⁺ uptake across the basolateral membrane. This uptake raises the intracellular [K+] and increases the electrochemical driving force for K⁺ exit across the apical membrane.
• Second, hyperkalemia also increases the permeability of the apical membrane to K⁺. Third, hyperkalemia stimulates aldosterone secretion by the adrenal cortex, which acts synergistically with the plasma [K⁺] to stimulate K⁺ secretion.
• Fourth, hyperkalemia also increases the flow rate of tubular fluid, which stimulates K⁺ secretion by the distal tubule and collecting duct.
• Hypokalemia (e.g., caused by a low-K⁺ diet or K⁺ loss in diarrhea) decreases K⁺ secretion by actions opposite to those described for hyperkalemia.
• Hence hypokalemia inhibits Na+-K+-ATPase, decreases the electrochemical driving force for K⁺ efflux across the apical membrane, reduces the permeability of the apical membrane to K⁺, and reduces plasma aldosterone levels.

“Symptoms and treatment of hyperkalemia (high potassium)”

The relationship between plasma K⁺ concentration ([K⁺]) and K+ secretion by the distal tubule and the cortical collecting duct.

• Chronic hypokalemia—that is, plasma K⁺ concentration ([K⁺]) <3.5 mEq/L—occurs most often in patients who receive diuretics for hypertension.
• Thus the excretion of K⁺ by the kidneys exceeds the dietary intake of K⁺. Hypokalemia also occurs in patients who vomit, have nasogastric suction, have diarrhea, abuse laxatives, or have hyperaldosteronism.
• Vomiting, nasogastric suction, diuretics, and diarrhea all can decrease the extracellular fluid volume, which in turn stimulates aldosterone secretion (see Chapter 6). Because aldosterone stimulates K⁺ excretion by the kidneys, its action contributes to the development of hypokalemia.
• Chronic hyperkalemia (plasma [K⁺] >5.0 mEq/L) occurs most frequently in persons with reduced urine flow, low plasma aldosterone levels, and renal disease in which the glomerular filtration rate falls below 20% of normal.
• In these persons, hyperkalemia occurs because the excretion of K⁺ by the kidneys is less than the dietary intake of K⁺. Less common causes for hyperkalemia occur in people with deficiencies of insulin, epinephrine, and aldosterone secretion or people with metabolic acidosis caused by inorganic acids.

“How do potassium imbalances affect heart function?”

Aldosterone

A chronic (i.e., 24 hours or more) elevation in the plasma aldosterone concentration enhances K⁺ secretion across principal cells in the distal tubule and collecting duct (Figure 7-7) by five mechanisms:

1. Increasing the amount of Na⁺-K⁺-ATPase in the basolateral membrane;
2. Increasing the expression of the sodium channel (ENaC) in the apical cell membrane;
3. Elevating serum glucocorticoid stimulated kinase (Sgk1) levels, which also increases the expression of ENaC in the apical membrane and activates K⁺ channels;
4. Stimulating channel activating protease 1 (CAP1, also called prostate), which directly activates ENaC; and
5. Stimulating the permeability of the apical membrane to K⁺.

The cellular mechanisms by which aldosterone affects the expression and activity of Na+-K⁺-ATPase and ENaC (preceding actions 1 to 4) have been described (see Chapter 4). Aldosterone increases the apical membrane K⁺ permeability by increasing the number of K⁺ channels in the membrane.

“Role of potassium balance in managing hypertension”

• However, the cellular mechanisms involved in this response are not completely known. Increased expression of Na+- K⁺-ATPase facilitates K⁺ uptake across the basolateral membrane into cells and thereby elevates intracellular [K⁺].
• The increase in the number and activity of Na+ channels enhances Na+ entry into the cell from the tubule fluid, an effect that depolarizes the apical membrane voltage. The depolarization of the apical membrane and increased intracellular [Kv] enhance the electrochemical driving force for K⁺ secretion from the cell into the tubule fluid.
• Taken together, these actions increase the cell [K⁺] and enhance the driving force for K+ exit across the apical membrane. Aldosterone secretion is increased by hyperkalemia and by angiotensin II (after activation of the renin-angiotensin system).
• Aldosterone secretion is decreased by hypokalemia and natriuretic peptides released from the heart.
• Although an acute increase in aldosterone levels (i.e., within hours) enhances the activity of Na+-K⁺– ATPase, K⁺ excretion does not increase.

The reason for this phenomenon is related to the effect of aldosterone on Na+ reabsorption and tubular flow. Aldosterone stimulates Na+ reabsorption and water reabsorption and thus decreases tubular flow. The decrease in flow in turn decreases K⁺ secretion (discussed in more detail later in this chapter). However, chronic stimulation of

“Complications of untreated potassium imbalances”

The Relationship Between Plasma Aldosterone And K⁺ Secretion By The Distal Tubule And The Cortical Collecting Duct. Note That K⁺ Secretion Is Increased Further When The Plasma K⁺ Concentration ([K] P) Is Increased.

Na+ reabsorption expands the ECF and thereby returns tubular flow to normal. These actions allow the direct stimulatory effect of aldosterone on the distal tubule and collecting duct to enhance K⁺ excretion.

Arginine Vasopressin

Although AVP does not affect net urinary K⁺ excretion, this hormone does stimulate K+ secretion by the distal tubule and collecting duct (Figure 7-8). AVP increases the electrochemical driving force for K+ exit across the apical membrane of principal cells by stimulating Na+ uptake across the apical membrane of principal cells.

• The increased Na+ uptake reduces the electrochemical driving force for K⁺ exit across the apical membrane (i.e., the interior of the cell becomes less negatively charged). Despite this effect, AVP does not change K⁺ secretion by these nephron segments.
• The reason for this phenomenon is related to the effect of AVP on tubular fluid. AVP decreases tubular fluid flow by stimulating water reabsorption.
• The decrease in tubular flow in turn reduces K⁺ secretion (explained later in this chapter). The inhibitory effect of decreased flow of tubular fluid offsets the stimulatory effect of AVP on the electrochemical driving force for K⁺ exit across the apical membrane.
• If AVP did not increase the electrochemical driving force favoring K⁺ secretion, urinary K⁺ excretion would decrease as AVP levels increase and urinary flow rates decrease. Hence K⁺ balance would change in response to alterations in water balance.
• Thus the effects of AVP on the electrochemical driving force for K⁺ exit across the apical membrane and tubule flow enable urinary K⁺ excretion to be maintained constant despite wide fluctuations in water excretion.

“Pathophysiology of potassium imbalances explained”

Factors That Perturb K⁺ Excretion

Whereas plasma [K⁺], aldosterone, and AVP play important roles in regulating K⁺ balance, the factors and hormones discussed next perturb K+ balance

Flow of Tubular Fluid

A rise in the flow of tubular fluid (e.g., with diuretic treatment and ECF volume expansion) stimulates K⁺ secretion within minutes, whereas a fall (e.g., ECF

“Emerging research on potassium regulation mechanisms”

Opposing Effects Of Arginine Vasopressin (AVP) On K⁺ Secretion By The Distal Tubule (Dt) And Cortical Collecting Duct (Ccd). Secretion Is Stimulated By An Increase In The Electrochemical Gradient For K⁺ Across The Apical Membrane And By An Increase In The K⁺ Permeability Of The Apical Membrane. In Contrast, Secretion Is Reduced By A Fall In The Flow Rate Of Tubular Fluid. Because These Effects Oppose Each Other, Net K+ Secretion Is Not Affected By Avp.

“Case studies on potassium balance outcomes”

Relationship Between Tubular Flow Rate And K⁺ Secretion By The Distal Tubule And Cortical Collecting Duct. A Diet High In K+ Increases The Slope Of The Relationship Between Flw Rate And Secretion And Increases.

• The Maximum Rate Of Secretion. A Diet Low In K⁺ Has The Opposite Effects. The Shaded Bar Indicates The Flw Rate Under Most Physiologic Conditions.
• volume contraction caused by hemorrhage, severe vomiting, or diarrhea) reduces K⁺ secretion by the distal tubule and collecting duct. Increments in tubular fluid are more effective in stimulating K⁺ secretion as dietary K⁺ intake is increased. Studies of the primary cilium in principal cells have elucidated some of the mechanisms whereby increased flow stimulates K⁺ secretion.
• As described in Chapter 2, increased flow bends the primary cilium in principal cells, which activates the PKD1/PKD2 Ca++ conducting channel complex.
• This mechanism allows more Ca++ to enter principal cells and increases intracellular [Ca++]. The increase in [Ca++] activates BK channels in the apical plasma membrane, which enhances K⁺ secretion from the cell into the tubule fluid. Increased flow also activates BK-mediated K⁺ secretion by intercalated cells.
• Increased flow also may stimulate K⁺ secretion by other mechanisms. As flow increases, for example, following the administration of diuretics or as the result of an increase in the ECF volume, so does the Na+ concentration of tubule fluid.
• This increase in Na+ concentration ([Na+]) facilitates Na+ entry across the apical membrane of the distal tubule and collecting duct cells, thereby decreasing the interior negative membrane potential of the cell.
• This depolarization of the cell membrane potential increases the electrochemical driving force that promotes K⁺ secretion across the apical cell membrane into the tubule fluid. In addition, increased Na+ uptake into cells activates the Na+-K⁺-ATPase in the basolateral membrane, thereby increasing K⁺ uptake across the basolateral membrane and elevating cells [K⁺].
• However, it is important to note that an increase in flow rate during a water diuresis does not have a significant effect on K⁺ excretion (see Figure 7-9), most likely because, during a water diuresis, the [Na+] of tubule fluid does not increase as flow rises.

“Complications of ignoring potassium imbalances”

Acid-Base Balance

Another factor that modulates K⁺ secretion is the [H+] of the ECF (Figure 7-10). Acute alterations (within minutes to hours) in the pH of the plasma influence K+ secretion by the distal tubule and collecting duct. Alkalosis (i.e., a plasma pH above normal) increases K⁺ secretion, whereas acidosis (i.e., a plasma pH below normal) decreases it. An acute acidosis reduces K+ secretion by two mechanisms:

1. It inhibits Na+-K⁺-ATPase and thereby reduces the cell [K+] and the electrochemical driving force for K+ exit across the apical membrane, and
2. It reduces the permeability of the apical membrane to K⁺. Alkalosis has the opposite effect.

The effect of metabolic acidosis on K⁺ excretion is time-dependent. When metabolic acidosis lasts for several days, urinary K+ excretion is stimulated (Figure 7-11). This stimulation occurs because chronic metabolic acidosis decreases the reabsorption of water and solutes (e.g., sodium chloride [NaCl]) by the

• Renal outer medullary K⁺ (ROMK) (KCNJ1) channels in the apical membrane of principal cells mediate K⁺ secretion. Four ROMK subunits make up a single channel. Interestingly, the knockout of the KCNJ1 gene (ROMK) causes increased sodium chloride (NaCl) and K+ excretion by the kidneys, leading to reduced extracellular fluid volume and hypokalemia.
• Although this effect is somewhat perplexing, it should be noted that ROMK also is expressed in the apical membrane of the thick ascending limb of Henle’s loop, where it plays an important role in K⁺ recycling across the apical membrane, an effect that is critical for the operation of the Na+-K⁺-2Cl− symporter (see Chapter 4).
• In the absence of ROMK, NaCl reabsorption by the thick ascending limb is reduced, which leads to NaCl loss in the urine. Reduction of NaCl reabsorption by the thick ascending limb also reduces the lumen-positive transepithelial voltage, which is the driving force for K⁺ reabsorption by this nephron segment.
• Thus the reduction in paracellular K⁺ reabsorption by the thick ascending limb increases urinary K+ excretion, even when the cortical collecting duct is unable to secrete the normal amount of K+ because of a lack of ROMK channels.
• The cortical collecting duct, however, does secrete K⁺ even in ROMK knockout mice through the flow and Ca++-dependent BK channels and by the operation of a K+-Cl− symporter expressed in the apical membrane of principal cells.

“Advances in understanding potassium homeostasis”

Effect Of Plasma Ph On The Relationship Between Plasma K⁺ Concentration ([K⁺]) And K+ Secretion By The Distal Tubule And Collecting Duct.

Short-term versus long-term effect of metabolic acidosis on K⁺ excretion. ECV, Effective circulating volume; NaCl, sodium chloride; Na+-K⁺-ATPase, sodium–potassium–adenosine triphosphatase; [K⁺], K⁺ concentration.

Proximal Tubule By Inhibiting Na+-K⁺-Atpase. Hence The Flw Of Tubular Flid Is Augmented Along The Distal Tubule And Collecting Duct. The Inhibition Of Proximal Tubular Water And Nacl Reabsorption Also Decreases The Ecf Volume And Thereby Stimulates Aldosterone Secretion.

• In Addition, Chronic Acidosis, Caused By Inorganic Acids, Increases Plasma [K⁺], Which Stimulates Aldosterone Secretion. The Rise In Tubular Flid Flw, Plasma [K+], And Aldosterone Levels Offsets The Effects Of Acidosis On The Cell [K⁺] And Apical Membrane Permeability, And K+ Secretion Rises.
• Thus Metabolic Acidosis May Either Inhibit Or Stimulate K⁺ Excretion, Depending On The Duration Of The Disturbance.
• The cellular mechanisms whereby changes in the K⁺ content of the diet and acid-base balance regulate K+ secretion by the distal tubule and collecting duct have been elucidated.
• Elevated K⁺ intake increases K⁺ secretion by several mechanisms, all related to increased serum K+ concentration. Hyperkalemia increases the activity of the renal outer medullary K+ (ROMK) channel in the apical plasma membrane of principal cells.
• Moreover, hyperkalemia inhibits proximal tubule sodium chloride (NaCl) and water reabsorption, thereby increasing distal tubule and collecting duct flow rate, a potent stimulus to K⁺ secretion.
• Hyperkalemia also enhances aldosterone concentration, which increases K⁺ secretion by three mechanisms. First, aldosterone increases the number of K+ channels in the apical plasma membrane. Second, aldosterone stimulates K⁺ uptake across the basolateral membrane by enhancing the number of Na+-K⁺-ATPase pumps, thereby enhancing the electrochemical gradient driving K⁺ secretion across the apical membrane.
• Third, aldosterone increases Na+ entry across the apical membrane, which depolarizes the apical plasma membrane voltage, thereby increasing the electrochemical gradient, and promoting K⁺ secretion. A low-K⁺ diet dramatically reduces K⁺ secretion by the distal tubule and collecting duct by increasing the activity of protein tyrosine kinase, which causes
• ROMK channels are to be removed from the apical plasma membrane, thereby reducing K⁺ secretion. Acidosis decreases K⁺ secretion by inhibiting the activity of ROMK channels, whereas alkalosis stimulates K⁺ secretion by enhancing ROMK channel activity.

“Global prevalence of potassium disorders”

As noted, acute metabolic alkalosis stimulates K⁺ excretion. Chronic metabolic alkalosis, especially in association with ECF volume contraction, significantly increases renal K⁺ excretion because of the associated increased levels of aldosterone.

Glucocorticoids

Glucocorticoids increase urinary K⁺ excretion. This effect is in part mediated by an increase in the glomerular filtration rate, which enhances urinary flow rate, a potent stimulus of K⁺ excretion, and by stimulating Sgk1 activity (discussed in a previous section).

• As discussed earlier, the rate of urinary K⁺ excretion is frequently determined by simultaneous changes in hormone levels, acid-base balance, or the flow rate of tubule fluid (Table 7-1).
• The powerful effect of flow often enhances or opposes the response of the distal tubule and collecting duct to hormones and changes in acid-base balance. This interaction can be beneficial in the case of hyperkalemia, in which the change in flow enhances K⁺ excretion and thereby facilitates K⁺ homeostasis.
• However, this interaction also can be detrimental, as in the case of alkalosis, in which changes in flow and acid-base status alter K⁺ homeostasis.

Table 7-1

Effects Of Hormones And Other Factors On K⁺ Secretion By The Distal Tubule And Collecting Duct And On Urinary K⁺ Excretion

The post Regulation Of Potassium Balance appeared first on BDS Notes.

Structure and function are closely linked in the kidneys. Consequently, an appreciation of the gross anatomic and histologic features of the kidneys is a prerequisite for an understanding of their function.

Structure Of The Kidneys

Gross Anatomy

The kidneys are paired organs that lie on the posterior wall of the abdomen behind the peritoneum on either side of the vertebral column.

In the adult human, each kidney weighs between 115 and 170 g and is approximately 11 cm long, 6 cm wide, and 3 cm thick.

The gross anatomic features of the human kidney are illustrated in 1. The medial side of each kidney contains an indentation, through which passes the renal artery and vein, nerves, and pelvis.

If a kidney were cut in half, two regions would be evident: an outer region called the cortex and an inner region called the medulla.

The cortex and medulla are composed of nephrons (the functional units of the kidney), blood vessels, lymphatics, and nerves. The medulla in the human kidney is divided into conical masses called renal pyramids.

“What is the structure and function of the kidneys?”

The base of each pyramid originates at the corticomedullary border, and the apex terminates in a papilla, which lies within a minor calyx. Minor calyces collect urine from each papilla.

The numerous minor calyces expand into two or three open-ended pouches, which are the major calyces. The major calyces in turn feed into the pelvis.

The pelvis represents the upper, expanded region of the ureter, which carries urine from the pelvis to the urinary bladder.

The walls of the calyces, pelvis, and ureters contain smooth muscle that contracts to propel the urine toward the urinary bladder.

“Understanding the role of kidneys in human physiology”

The blood flow to the two kidneys is equal to about 25% (1.25 L/min) of the cardiac output in resting individuals. However, the kidneys constitute less than 0.5% of total body weight.

As illustrated, the renal artery branches progressively to form the interlobar artery, the arcuate artery, the interlobular artery, and the afferent arteriole, which leads into the glomerular capillaries.

The glomerular capillaries come together to form the efferent arteriole, which leads into a second capillary network, the peritubular capillaries, which supply blood to the nephron.

The vessels of the venous system run parallel to the arterial vessels and progressively form the interlobular vein, arcuate vein, interlobar vein, and renal vein, which courses beside the ureter.

Ultrastructure of the Nephron

The functional unit of the kidneys is the nephron. Each human kidney contains approximately 1.2 million nephrons, which are hollow tubes composed of a single cell layer.

The nephron consists of a renal corpuscle, proximal tubule, loop of Henle, distal tubule, and collecting duct system.

The renal corpuscle consists of glomerular capillaries and Bowman’s capsule. The proximal tubule initially forms several coils, followed by a straight piece that descends toward the medulla.

The next segment is the loop of Henle, which is composed of the straight part of the proximal tubule, the descending thin limb (which ends in a hairpin turn).

The ascending thin limb (only in nephrons with long loops of Henle), and the thick ascending limb. Near the end of the thick ascending limb, the nephron passes between the afferent and efferent arterioles of the same nephron.

“How do the kidneys maintain homeostasis in the body?”

This short segment of the thick ascending limb that touches the glomerulus is called the macula densa.

The distal tubule begins a short distance beyond the macula densa and extends to the point in the cortex where two or more nephrons join to form a cortical collecting duct.

The cortical collecting duct enters the medulla and becomes the outer medullary collecting duct and then the inner medullary collecting duct.

Each nephron segment is made up of cells that are uniquely suited to perform specific transport functions.

Proximal tubule cells have an extensively amplified apical membrane (the urine side of the cell) called the brush border, which is present only in the proximal tubule of the nephron.

The basolateral membrane (the blood side of the cell) is highly invaginated. These invaginations contain many mitochondria.

In contrast, the descending and ascending thin limbs of Henle’s loop have poorly developed apical and basolateral surfaces and few mitochondria.

“Importance of studying kidney structure and function”

The cells of the thick ascending limb and the distal tubule have abundant mitochondria and extensive infoldings of the basolateral membrane.

The collecting duct is composed of two cell types: principal cells and intercalated cells. Principal cells have a moderately invaginated basolateral membrane and contain few mitochondria.

Principal cells play an important role in sodium chloride (NaCl) reabsorption and K⁺ secretion.

Intercalated cells, which play an important role in regulating acid-base balance, have a high density of mitochondria.

One population of intercalated cells secretes H⁺ (i.e., reabsorbs bicarbonate [HCO₃^–]) and a second population of intercalated cells secretes HCO^–₃.

The final segment of the nephron, the inner medullary collecting duct, is composed of inner medullary collecting duct cells.

Cells of the inner medullary collecting duct have poorly developed apical and basolateral surfaces and few mitochondria.

Except for intercalated cells, all cells in the nephron have in the apical plasma membrane a single nonmotile primary cilium that protrudes into the tubule flid.

Primary cilia are mechanosensors (i.e., they sense changes in the flow rate of tubule fluid) and chemosensors (i.e., they sense or respond to compounds in the surrounding fluid).

They initiate Ca⁺⁺-dependent signaling pathways, including those that control kidney cell function, proliferation, differentiation, and apoptosis (i.e., programmed cell death).

“Common parts of the kidney explained”

Polycystin 1 (encoded by the PKD1 gene) and polycystin 2 (encoded by the PKD2 gene) are expressed in the membrane of primary cilia, and the PKD1/PKD2 complex mediates the entry of Ca++ into cells.

PKD1 and PKD2 are thought to play an important role in flow-dependent K⁺ secretion by principal cells of the collecting duct.

Increased flow of tubule fluid in the collecting duct is a strong stimulus for K⁺ secretion.

Increased flow bends the primary cilium in principal cells, which activates the PKD1/PKD2 Ca⁺⁺ conducting channel complex, allowing Ca⁺⁺ to enter the cell and increase intracellular [Ca⁺⁺].

The increase in [Ca⁺⁺ activates K⁺ channels in the apical plasma membrane, which enhances K⁺ secretion from the cell into the tubule fluid.

Nephrons may be subdivided into superficial and juxtamedullary types. The glomerulus of each superficial nephron is located in the outer region of the cortex.

Its loop of Henle is short, and its efferent arteriole branches into peritubular capillaries that surround the nephron segments of its own and adjacent nephrons.

This capillary network conveys oxygen and important nutrients to the nephron segments in the cortex and delivers substances to the nephron for secretion (i.e., the movement of a substance from the blood into the tubular fluid).

“Anatomy of the nephron: Structure and function”

And serves as a pathway for the return of reabsorbed water and solutes to the circulatory system. A few species, including humans, also possess very short superficial nephrons whose Henle’s loops never enter the medulla.

Autosomal dominant polycystic kidney disease (ADPKD), which is the most common inherited kidney disease, occurs in 1 in 1000 people.

Approximately 12.5 million people worldwide have ADPKD, which is caused primarily by mutations in the genes PKD1 (85% of cases) and PKD2 (~15% of cases).

The major phenotype of ADPKD is an enlargement of the kidneys related to the presence of hundreds to thousands of renal cysts that can be as large as 20 cm in diameter.

Cysts also are seen in the liver and other organs. About 50% of patients with ADPKD progress to renal failure by the age of 60 years.

Although it is not clear how mutations in PKD1 and PKD2 cause ADPKD, renal cyst formation results from defects in Ca⁺⁺ uptake that lead to alterations in Ca++-dependent signaling pathways, including those that control kidney cell proliferation, differentiation, and apoptosis.

The glomerulus of each juxtamedullary nephron is located in the region of the cortex adjacent to the medulla.

In comparison with the superficial nephrons, the juxtamedullary nephrons differ anatomically in two important ways: the loop of Henle is longer and extends deeper into the medulla.

The efferent arteriole forms not only a network of peritubular capillaries but also a series of vascular loops called the vasa recta.

The vasa recta descend into the medulla, where they form capillary networks that surround the collecting ducts and ascending limbs of the loop of Henle. The blood returns to the cortex in the ascending vasa recta.

Although less than 0.7% of the blood enters the vasa recta, these vessels subserve important functions in the renal medulla, including

1. Conveying oxygen and important nutrients to nephron segments,
2. Delivering substances to the nephron for secretion,
3. Serving as a pathway for the return of reabsorbed water and solutes to the circulatory system, and
4. Concentrating and diluting the urine.

“Role of the glomerulus in kidney filtration”

Ultrastructure Of The Glomerulus

The first step in urine formation begins with the passive movement of a plasma ultrafiltrate from the glomerular capillaries into Bowman’s space.

The term ultrafiltration refers to the passive movement of fluid that is similar in composition to plasma.

Except that the protein concentration in the ultrafiltrate is lower than that in the plasma, from the glomerular capillaries into Bowman’s space.

To appreciate the process of ultrafiltration, one must understand the anatomy of the glomerulus.

The glomerulus consists of a network of capillaries supplied by the afferent arteriole and drained by the efferent arteriole.

“How does the renal tubule work in urine formation?”

During embryologic development, the glomerular capillaries press into the closed end of the proximal tubule, forming Bowman’s capsule.

As the epithelial cells thin on the outside circumference of Bowman’s capsule, they form the parietal epithelium.

“Structure of the renal cortex and medulla explained”

The epithelial cells in contact with the capillaries thicken and develop into podocytes, which form the visceral layer of Bowman’s capsule.

The space between the visceral layer and the parietal layer is Bowman’s space, which at the urinary pole (i.e., where the proximal tubule joins Bowman’s capsule) of the glomerulus becomes the lumen of the proximal tubule.

“Biomechanics of blood flow in the kidneys”

The endothelial cells of glomerular capillaries are covered by a basement membrane, which is surrounded by podocytes. The capillary endothelium, basement membrane, and foot processes of podocytes form the so-called filtration barrier.

The endothelium is fenestrated (i.e., it contains 700-Å holes where 1 Å = 10^-10 m) and is freely permeable to water, and small solutes (such as Na⁺, urea, and glucose).

And small proteins but are not permeable to large proteins, red blood cells, white blood cells, or platelets.

Because endothelial cells express glycoproteins on their surface, they minimize the filtration into Bowman’s space of albumin, the most abundant plasma protein, and small plasma proteins.

In addition to their role as a barrier to filtration, the endothelial cells synthesize a number of vasoactive substances (For Example., nitric oxide, a vasodilator, and endothelin-1, a vasoconstrictor) that are important in controlling renal plasma flow.

The basement membrane, which is a porous matrix of negatively charged proteins, including type 4 collagen, laminin, the proteoglycans agrin and perlecan, and fibronectin, is also an important filtration barrier to plasma proteins.

“Role of kidneys in regulating blood pressure”

The podocytes have long fingerlike processes that completely encircle the outer surface of the capillaries.

The processes of podocytes interdigitate to cover the basement membrane and are separated by apparent gaps called filtration slits.

Each filtration slit is bridged by a thin diaphragm, the filtration slit diaphragm, which appears as a continuous structure when viewed by electron microscopy.

The filtration slit diaphragm is composed of several proteins including nephrin, NEPH-1, and podocin, along with intracellular proteins that associate with slit diaphragm proteins, including CD2-AP and α-actinin 4 (ACTN4).

Filtration slits, which function primarily as a size-selective filter, minimize the filtration of proteins and macromolecules that cross the basement membrane from entering Bowman’s space.

“How do kidneys control fluid and electrolyte balance?”

Nephrotic syndrome is produced by a variety of disorders and is characterized by an increase in the permeability of the glomerular capillaries to proteins and by a loss of normal podocyte structure, including effacement (i.e., thinning) of foot processes.

The augmented permeability to proteins results in an increase in urinary protein excretion (proteinuria). Thus the appearance of proteins in the urine can indicate kidney disease.

Hypoproteinemia often develops in persons with this syndrome as a result of proteinuria. In addition, generalized edema commonly is seen in
persons with nephrotic syndrome.

Mutations in several genes that encode slit diaphragm proteins, including nephrin, NEPH-1, and podocin, along with intracellular proteins that associate with slit diaphragm proteins.

Including CD2-AP and α-actinin 4 (ACTN4), or a knockout of these genes in mice, cause proteinuria and kidney disease.

For example, mutations in the nephrin gene (NPHS1) lead to abnormal or absent slit diaphragms, causing massive proteinuria and renal failure (i.e., congenital nephrotic syndrome).

In addition, mutations in the podocin gene (NPHS2) cause autosomal recessive, steroid-resistant nephrotic syndrome.

These naturally occurring mutations and knockout studies in mice demonstrate that nephrin, NEPH-1, podocin, CD2-AP, and α-actinin 4 play key roles in podocyte structure and function.

Alport syndrome is characterized by hematuria (i.e., blood in the urine) and progressive glomerulonephritis (i.e., inflammation of the glomerular capillaries) and accounts for 1% to 2% of all cases of end-stage renal disease.

Alport syndrome is caused by mutations in type 4 collagen, a major component of the glomerular basement membrane.

In about 80% of patients with Alport syndrome, the disease is X-linked with mutations in the COL4A5 gene.

Fifteen percent of patients also have mutations in type 4 collagen genes (COL4A3 and COL4A4); six have been identified, but the mode of inheritance is autosomal recessive.

The remaining 5% of patients with Alport syndrome have autosomal dominant disease that arises from heterozygous mutations in the COL4A3 or COL4A4 genes.

In persons with Alport syndrome, the glomerular basement membrane becomes irregular in thickness and fails to serve as an effective filtration barrier to blood cells and protein.

Another important component of the renal corpuscle is the mesangium, which consists of mesangial cells and the mesangial matrix.

“Impact of kidneys on acid-base regulation”

“Kidneys and their role in waste excretion”

Mesangial cells are involved in the development of immune complex-mediated glomerular disease.

Because the glomerular basement membrane does not completely surround all glomerular capillaries, some immune complexes can enter the mesangial area without crossing the glomerular basement membrane.

Accumulation of immune complexes induces the infiltration of inflmmatory cells into the mesangium and promotes the production of proinflammatory cytokines and autacoids by cells in the mesangium.

These cytokines and autacoids enhance the inflmmatory response. This inflmmatory response can lead to cell death, scarring and eventually obliterating the glomerulus.

Mesangial cells, which possess many properties of smooth muscle cells, provide structural support for the glomerular capillaries and secrete the extracellular matrix.

Exhibit phagocytic activity that removes macromolecules from the mesangium, and secretes prostaglandins and proinflammatory cytokines.

Because they also contract and are adjacent to glomerular capillaries, mesangial cells may influence the glomerular filtration rate (GFR) by regulating blood flow through the glomerular capillaries or by altering the capillary surface area.

Mesangial cells located outside the glomerulus (between the afferent and efferent arterioles) are called extraglomerular mesangial cells.

“Can kidney dysfunction affect hormone production?”

Ultrastructure Of The Juxtaglomerular Apparatus

The juxtaglomerular apparatus (JGA) is one component of an important feedback mechanism, the tubuloglomerular feedback mechanism, that is described. The following structures make up the JGA:

1. The macula densa of the thick ascending limb
2. The extraglomerular mesangial cells
3. The renin- and angiotensin II–produce granular cells of the afferent arteriole.

The cells of the macula densa represent a morphologically distinct region of the thick ascending limb. This region passes through the angle formed by the afferent and efferent arterioles of the same nephron.

The cells of the macula densa are in contact with the extraglomerular mesangial cells and the granular cells of the afferent arterioles.

Granular cells of the afferent arterioles are derived from metanephric mesenchymal cells. They contain smooth muscle myofilaments and they manufacture, store, and release renin.

Renin is involved in the formation of angiotensin II and ultimately in the secretion of aldosterone.

The JGA is one component of the tubuloglomerular feedback mechanism that is involved in the autoregulation of renal blood flow and the GFR.

“Steps in the filtration process of the kidneys”

Innervation Of The Kidneys

Renal nerves regulate renal blood flow, GFR, and salt and water reabsorption by the nephron. The nerve supply to the kidneys consists of sympathetic nerve fibers that originate in the celiac plexus.

No parasympathetic innervation occurs. Adrenergic fibers that innervate the kidneys release norepinephrine.

The adrenergic fibers lie adjacent to the smooth muscle cells of the major branches of the renal artery (the interlobar, arcuate, and interlobular arteries) and the afferent and efferent arterioles.

Moreover, sympathetic nerves innervate the renin-producing granular cells of the afferent arterioles. Renin secretion is stimulated by increased sympathetic activity.

Nerve fibers also innervate the proximal tubule, loop of Henle, distal tubule, and collecting duct; activation of these nerves enhances Na⁺ reabsorption by these nephron segments.

The post Structure And Function Of The Kidneys appeared first on BDS Notes.

As described, water constitutes approximately 60% of the healthy adult human body. Body water is divided into two compartments (i.e., intracellular fluid and extracellular fluid [ECF]), which are in osmotic equilibrium.

“What is the regulation of body fluid osmolality?”

• Water intake into the body generally occurs orally, and the water ingested is absorbed into the ECF by the gastrointestinal tract via a mechanism similar to that which mediates water absorption by the proximal tubule.
• However, in clinical situations, intravenous infusion is an important route of water entry. Regardless of the route of entry (oral versus intravenous), water first enters the ECF and then equilibrates with the intracellular fluid. The
• kidneys are responsible for regulating water balance and under most conditions is the major route for the elimination of water from the body (Table 5-1). Other routes of water loss from the body include evaporation from the cells of the skin and respiratory passages.
• Collectively, water loss by these routes is termed insensible water loss because people are unaware of its occurrence. The production of sweat accounts for the loss of additional water.
• Water loss by this mechanism can increase dramatically in a hot environment, with exercise, or in the presence of fever. Finally, water can be lost from the gastrointestinal tract.
• Fecal water loss is normally small (~100 mL/day) but can increase dramatically with diarrhea (for example., 20 L/day in persons with cholera). Vomiting also can cause gastrointestinal water loss.

Normal Routes of Water Gain and Loss in Adults at Room Temperature (23°C):

“Understanding the role of water balance in human physiology”

Effect of Environmental Temperature and Exercise on Water Loss and Intake in Adults:

“How does the body regulate osmolality and water balance?”

Although water loss from sweating, defecation, and evaporation from the lungs and skin can vary depending on the environmental conditions or during pathologic conditions, the loss of water by these routes cannot be regulated.

• In contrast, the renal excretion of water is tightly regulated to maintain whole-body water balance. The maintenance of water balance requires that water intake and loss from the body are precisely matched. If intake exceeds losses, a positive water balance exists.
• Conversely, when intake is less than losses, a negative water balance exists.
  When water intake is low or water losses increase, the kidneys conserve water by producing a small volume of hyperosmotic urine concerning plasma.
• When water intake is high, a large volume of hypoosmotic urine is produced. In a healthy person, the urine osmolality (U_osm) can vary from approximately 50 to 1200 mOsm/kg H₂O, and the corresponding urine volume can vary from approximately 18 to 0.5 L/day.
• It is important to recognize that disorders of water balance are manifested by alterations in the body fluid osmolality, which usually are measured by changes in

“Importance of maintaining body fluid osmolality”

When plasma osmolality (P_osm) is reduced (i.e., hypos- molality), water moves from the extracellular fluid into cells, causing them to swell.

• Symptoms associated with hypo osmolality are related primarily to swelling of brain cells. For example, a rapid decrease in P_osm can alter neurologic function and thereby cause nausea, malaise, headache, confusion, lethargy, seizures, and coma.
• When P_osm is increased (i.e., hyperosmolality), water is lost from cells, causing them to shrink. The symptoms of an increase in P_osm also are primarily neurologic and include lethargy, weakness, seizures, coma, and even death.
• The symptoms associated with changes in body fluid osmolality vary depending on how quickly osmolality is changed. Rapid changes in osmolality (i.e., over hours) are less well tolerated than changes that occur more gradually (i.e., over days to weeks).
• Indeed, when alterations in body fluid osmolality have developed over an extended period, such persons may be entirely asymptomatic.
• This situation reflects the ability of cells over time either to eliminate intracellular osmoles, as occurs with hyperosmolality, or to generate new intracellular osmoles in response to hyperosmolality and thus minimize changes in cell volume of the neurons.
• This ability has important clinical implications when treating a patient with an abnormal plasma osmolality. For example, rapid correction of the osmolality of a person who has had long-standing hyperosmolality of the body fluids can lead to the development of osmotic demyelination syndrome.

“Common mechanisms of water balance regulation explained”

The syndrome can result in paralysis of multiple muscle groups and can be fatal.

“Role of antidiuretic hormone (ADH) in osmolality regulation”

Plasma osmolality (P_osm). Because the major determinant of plasma osmolality is Na⁺ (with its anions Cl- and HCO^–₃), these disorders also result in alterations in the plasma [Na⁺]

• When an abnormal plasma [Na⁺] is observed in an individual, it is tempting to suspect a problem in Na⁺ balance. However, the problem usually is related to water balance, not Na⁺ balance.
• As described, changes in Na⁺ balance result in alterations in the volume of the ECF, not its osmolality.
• Under steady-state conditions, the kidneys control water excretion independently of their ability to control the excretion of various other physiologically important substances such as Na⁺, K⁺, and urea
• Indeed, this ability is necessary for survival because it allows water balance to be achieved without upsetting the other homeostatic functions of the kidneys.
• This chapter discusses the mechanisms by which the kidneys maintain water balance by excreting either hypoosmotic (dilute) or hyperosmotic (concentrated) urine.

The control of arginine vasopressin (AVP) secretion and its important role in regulating the excretion of water by the kidneys are also explained.

Arginine Vasopressin

AVP, also known as antidiuretic hormone, acts on the kidneys to regulate the volume and osmolality of the urine.

• When plasma AVP levels are low, a large volume of urine is excreted (diuresis), diluting the urine.
• When plasma levels are high, a small volume of urine is excreted (antidiuresis), and the urine is concentrated.
• Illustrates the effect of AVP on the urine flow rate and osmolality. The excretion of

“How does ADH affect water reabsorption in the kidneys?”

As already noted, AVP does not appreciably alter the excretion of solute, which underscores the fact that AVP controls water excretion and maintains water balance without altering the excretion and homeostatic control of other substances.

• AVP is a small peptide that is nine amino acids in length. It is synthesized in neuroendocrine cells located within the supraoptic and paraventricular nuclei of the hypothalamus.
• The synthesized hormone is packaged in granules that are transported down the axon of the cell and stored in the nerve terminals located in the neurohypophysis (posterior pituitary).
• The anatomy of the hypothalamus and pituitary gland. The secretion of AVP by the posterior pituitary can be influenced by several factors.
• The two primary physiologic regulators of AVP secretion are the osmolality of the body fluids (osmotic) and the volume and pressure of the vascular system (hemodynamic). Other factors that can alter AVP secretion include nausea

Arginine Vasopressin At The Cellular Level: The gene for arginine vasopressin (AVP) is found on chromosome 20. It contains approximately 2000 base pairs with three exons and two introns.

• The gene codes for a 145 amino acid prohormone that consists of a signal peptide, the AVP molecule, neurophysin, and a glycopeptide (copeptin).
• As the cell processes the prohormone, the signal peptide is cleaved off in the rough endoplasmic reticulum. Once packaged in neurosecretory granules, the preprohormone is further cleaved into AVP, neurophysin, and copeptin molecules.
• The neurosecretory granules are then transported down the axon to the posterior pituitary and stored in the nerve endings until released.
• When the neurons are stimulated to secrete AVP, the action potential opens Ca++ channels in the nerve terminal, which raises the intracellular [Ca++] and causes exocytosis of the neurosecretory granules.
• All three peptides are secreted in this process. Neurophysin and copeptin do not have an identified physiologic function.
• (stimulates), atrial natriuretic peptide (inhibits), and angiotensin II (stimulates). Several drugs, prescription and nonprescription, also affect AVP secretion. For example, nicotine stimulates secretion, whereas ethanol inhibits secretion.

“Impact of aldosterone on osmolality and water balance”

Osmotic Control Of Arginine Vasopressin Secretion:

Changes in the osmolality of body fluids play the most important role in regulating AVP secretion; changes as minor as 1% are sufficient to alter it significantly.

• Although the neurons in the supraoptic and paraventricular nuclei respond to changes in body fluid osmolality by altering their secretion of AVP, it is clear that separate cells exist in the anterior hypothalamus that sense changes in body fluid osmolality and regulate the activity of the AVP-secreting neurons.
• These cells, termed osmoreceptors, appear to sense changes in body fluid osmolality by either shrinking or swelling.

“Biomechanics of osmosis in body fluids explained”

The osmoreceptors respond only to solutes in plasma that are effective osmoles. For example, urea is an ineffective osmole when the function of osmoreceptors is considered.

• Thus elevation of the plasma urea concentration alone has little or no effect on AVP secretion.
• When the effective osmolality of the plasma increases, the osmoreceptors send signals to the AVP synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus, and AVP synthesis and secretion are stimulated.
• Conversely, when the effective osmolality of the plasma is reduced, secretion is inhibited.
• Because AVP is rapidly degraded in the plasma, circulating levels can be reduced to zero within minutes after secretion is inhibited. As a result, the AVP system can respond rapidly to fluctuations in body fluid osmolality.

Illustrates the effect of changes in plasma osmolality on circulating AVP levels. The set point of the system is the plasma osmolality value at which AVP secretion begins to increase.

• Below this set point, virtually no AVP is released. Above this set point, the slope of the relationship is quite steep and accounts for the sensitivity of this system. The set point varies among individuals and is genetically determined.
• In healthy adults, it varies from 275 to 290 mOsm/kg H₂O (average ~280 to 285 mOsm/kg H₂O). As described later in this chapter, the set point shifts in response to changes in blood volume and pressure.
• It also shifts during pregnancy, with the osmolality of the mother’s body fluids decreasing during the third trimester.
• The reasons for the shift of the set point during pregnancy are not completely known but likely involve hormones (for example., relaxin) whose circulating levels are elevated at this stage of pregnancy.

Hemodynamic Control Of Arginine Vasopressin Secretion:

A decrease in blood volume or pressure also stimulates AVP secretion.

The receptors responsible for this response are located in both the low-pressure (left atrium and large pulmonary vessels) and the high-pressure (aortic arch and carotid sinus) sides of the circulatory system.

“Comparison of osmolality regulation in health vs disease”

Because the low-pressure receptors are located in the high-compliance side of the circulatory system (i.e., venous) and the majority of blood is in the venous side of the circulatory system, these low-pressure receptors can be viewed as responding to overall vascular volume.

• The high-pressure receptors respond to arterial pressure. Both groups of receptors are sensitive to a stretch of the wall of the structure in which they are located (for example., the cardiac atrial wall and the wall of the aortic arch) and are termed baroreceptors.
• Signals from these receptors are carried in afferent fibers of the vagus and glossopharyngeal nerves to the brainstem (solitary tract nucleus of the medulla oblongata), which is part of the center that regulates heart rate and blood pressure.
• Signals then are relayed from the brainstem to the AVP secretory cells of the supraoptic and paraventricular hypothalamic nuclei.
• The sensitivity of the baroreceptor system is less than that of the osmoreceptors, and a 5% to 10% decrease in blood volume or pressure is required before AVP secretion is stimulated.

This phenomenon is illustrated, in B. Several substances have been shown to alter the secretion of AVP through their effects on blood pressure.

• These substances include bradykinin and histamine, which lower pressure and thus stimulate AVP secretion, and norepinephrine, which increases blood pressure and inhibits AVP secretion.
• Alterations in blood volume and pressure also affect the response to changes in body fluid osmolality.
• With a decrease in blood volume or pressure, the set point is shifted to lower osmolality values and the slope of the relationship is steeper.
• In terms of survival of the individual, this means that when faced with circulatory collapse, the kidneys continue to conserve water, even though by doing so they reduce the osmolality of the body fluids.
• With an increase in blood volume or pressure, the opposite occurs. The set point is shifted to higher osmolality values, and the slope is decreased.

Arginine Vasopressin Actions On The Kidneys:

The primary action of AVP on the kidneys is to increase the permeability of the collecting duct to water.

• In addition, and notably, AVP increases the permeability of the medullary portion of the collecting duct to urea.
• Lastly, AVP stimulates sodium chloride (NaCl) reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the cortical portion of the collecting duct.

Inadequate release of arginine vasopressin (AVP) from the posterior pituitary results in the excretion of large volumes of dilute urine (polyuria).

• To compensate for this loss of water, the individual must ingest large volumes of water (polydipsia) to maintain constant body fluid osmolality.
• If the individual is deprived of water, the body fluids become hyperosmotic. This condition is called central diabetes insipidus or pituitary diabetes insipidus.
• Central diabetes insipidus can be inherited, although this situation is rare. It occurs more commonly after head trauma and with brain neoplasms or infections.

“Mechanisms of water reabsorption in the nephron”

Persons with central diabetes insipidus have a urine-concentrating defect that can be corrected by the administration of exogenous AVP.

• The inherited (autosomal dominant) form of central diabetes insipidus is caused by a variety of mutations in the AVP gene.
• In patients with this form of central diabetes insipidus, mutations have been identified in all regions of the AVP gene (i.e., AVP, copeptin, and neurophysin).
• The most common mutation is found in the neurophysin portion of the gene. In each of these situations, defective trafficking of the peptide occurs, with abnormal accumulation in the endoplasmic reticulum.

It is believed that this abnormal accumulation in the endoplasmic reticulum results in the death of the AVP secretory cells of the supraoptic and paraventricular nuclei.

• The syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) is a common clinical problem characterized by plasma AVP levels that are elevated above what would be expected based on body fluid osmolality and blood volume and pressure—hence the term inappropriate ADH secretion.
• In addition, the collecting duct overexpresses water channels, thus augmenting the effect of AVP on the kidney. Persons with SIADH retain water, and their body fluids become progressively hypoosmotic.

In addition, their urine is more hyperosmotic than expected based on the low body fluid osmolality. SIADH can be caused by infections and neoplasms of the brain, drugs (for example., antitumor drugs), pulmonary diseases, and carcinoma of the lung.

• Many of these conditions stimulate AVP secretion by altering neural input to the AVP secretory cells. However, small cell carcinoma of the lung produces and secretes several peptides, including AVP.
• Recently, nonpeptide vasopressin receptor antagonists (for example., conivaptan and tolvaptan) have been developed that can be used to treat SIADH and other conditions in which AVP-dependent water retention by the kidneys occurs (for example., congestive heart failure and hepatic cirrhosis).

“How do the kidneys maintain osmolality balance?”

The actions of AVP on the water permeability of the collecting duct have been studied extensively. AVP binds to a receptor on the basolateral membrane of the cell. This receptor is termed the V2 receptor (i.e., vasopressin 2 receptor).

• Binding to this receptor, which is coupled to adenylyl cyclase through a stimulatory G protein (Gs), increases the intracellular levels of cyclic adenosine monophosphate (cAMP).
• The rise in intracellular cAMP activates protein kinase A, which ultimately increases the number of aquaporin (AQP)-2 water channels in the apical membrane of the cell and the synthesis of more AQP-2.
• With the removal of AVP, the number of AQP-2 water channels in the apical membrane is reduced, thereby rendering the membrane impermeable to water.
• Because the basolateral membrane is freely permeable to water because of the presence of AQP-3 and AQP-4 water channels, any water that enters the cell through apical membrane water channels exits across the basolateral membrane, resulting in net absorption of water from the tubule lumen.

“Role of the loop of Henle in concentrating urine”

AVP also increases the permeability of the terminal portion of the inner medullary collecting duct to urea. This increase in permeability results in an increase in urea reabsorption and an increase in the osmolality of the medullary interstitial fluid.

• The inner medullary collecting duct expresses two different urea transporters (UTs: UT-A1 and UT-A3. UT-A1 is found in the apical membrane and UT-A3 is found in the basolateral membrane.
• AVP, acting through adenylyl cyclase and the cAMP/protein kinase A cascade, increases the permeability of the apical membrane to urea.
• This increase in permeability is associated with phosphorylation of UT-A1 and UT-A3. Increasing the osmolality of the interstitial fluid of the renal medulla also increases the permeability of the collecting duct to urea.
• This effect is mediated by the phospholipase C pathway and involves protein kinase C phosphorylation. Thus this effect is separate from and additive to that of AVP.
• AVP also stimulates the reabsorption of NaCl by the thick ascending limb of Henle’s loop and by the distal tubule and cortical segment of the collecting duct.
• It is thought that stimulation of thick ascending limb NaCl transport, in particular, may help maintain the hyperosmotic medullary interstitium that is necessary for the absorption of water from the medullary portion of the collecting duct (discussed later in this chapter).

Arginine Vasopressin At The Cellular Level

The gene for the V₂ receptor is located on the X chromosome. It codes for a 371-amino-acid protein that is in the family of receptors that have seven membrane-spanning domains and are coupled to heterotrimeric G proteins.

• As binding of AVP to its receptor on the basolateral membrane activates adenylyl cyclase.
• The increase in intracellular cyclic adenosine monophosphate (cAMP) then activates protein kinase A, which results in phosphorylation of aquaporin (AQP)-2 water channels, which reduces the endocytic removal of AQP-2 from the apical membrane and also results in increased transcription of the AQP-2 gene through activation of a cAMP response element.
• AVP also increases the rate of insertion of vesicles containing AQP-2 into the apical membrane by facilitating their movement along microtubules driven by the molecular motor dynein.

Once near the apical membrane, proteins called SNAREs interact with vesicles containing AQP-2 and facilitate the fusion of these vesicles with the membrane.

• The net addition of AQP-2 to the apical membrane, resulting from reduced endocytosis and increased insertion, allows more water to enter the cell driven by the osmotic gradient (lumen osmolality < cell osmolality).
• The water then exits the cell across the basolateral membrane through AQP-3 and AQP-4 water channels, which are constitutively present in the basolateral membrane.
• When the V⁺ receptor is not occupied by AVP, clathrin-mediated endocytosis of AQP-2 is enhanced and the exocytic insertion of AQP-2 is reduced, which decreases the total number of AQP-2 channels in the apical membrane, rendering the apical membrane once again impermeable to water.

Recently, persons have been found who have activating (gain-of-function) mutations in the V₂ receptor gene. Thus the receptor is constitutively activated even in the absence of AVP.

• These persons have laboratory findings similar to those seen in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), including reduced plasma osmolality, hyponatremia (reduced plasma [Na⁺]), and urine more concentrated than would be expected from the reduced body fluid osmolality.
• However, unlike persons with SIADH, in whom circulating levels of AVP are elevated and thus responsible for water retention by the kidneys, these persons have undetectable levels of AVP in their plasma. This new clinical entity has been termed “nephrogenic syndrome of inappropriate antidiuresis.”
• The collecting ducts of some persons do not respond normally to arginine vasopressin (AVP). These persons cannot maximally concentrate their urine and consequently have polyuria and polydipsia.

“Impact of glomerular filtration rate (GFR) on water balance”

This clinical entity is termed nephrogenic diabetes insipidus to distinguish it from central diabetes insipidus. Nephrogenic diabetes insipidus can result from several systemic disorders and, more rarely, occurs as a result of inherited disorders.

• Many of the acquired forms of nephrogenic diabetes insipidus are the result of decreased expression of aquaporin-2 (AQP-2) in the collecting duct.
• Decreased expression of AQP-2 has been documented in the urine-concentrating defects associated with hypokalemia, lithium ingestion (some degree of nephrogenic diabetes insipidus develops in 35% of persons who take lithium for bipolar disorder), ureteral obstruction, a low-protein diet, and hypercalcemia. The inherited forms of nephrogenic diabetes insipidus reflect mutations in the AVP receptor (V₂ receptor) gene or the AQP-2 gene.
• Approximately 90% of hereditary forms of nephrogenic diabetes insipidus are the result of mutations in the V₂ receptor gene, with the other 10% being the result of mutations in the AQP-2 gene.

Because the gene for the V₂ receptor is located on the X chromosome, these inherited forms are X-linked. Most of these mutations result in trapping of the receptor in the endoplasmic reticulum of the cell; only a few cases result in the surface expression of a V₂ receptor that does not bind AVP.

• The gene coding for AQP-2 is located on chromosome 12 and is inherited as both an autosomal recessive and an autosomal dominant defect. As noted in Chapters 1 and 4, aquaporins exist as homotetramers.
• This homotetramer formation explains the difference between the two forms of nephrogenic diabetes insipidus. In the recessive form, heterozygotes produce both normal AQP-2 and defective AQP-2 molecules.
• The defective AQP-2 monomer is not delivered to the plasma membrane, and thus the homotetramers that do form contain only normal AQP-2 molecules.
• Accordingly, mutations in both alleles would be required to produce nephrogenic diabetes insipidus.
• In the autosomal dominant form, the defective monomers can form tetramers with normal monomers, as well as defective monomers. However, these tetramers cannot be delivered to the plasma membrane.

“How does the renal system respond to dehydration?”

Thirst

In addition to affecting the secretion of AVP, changes in plasma osmolality and blood volume or pressure lead to alterations in the perception of thirst.

• When body fluid osmolality is increased or the blood volume or pressure is reduced, a person perceives thirst. Of these stimuli, hypertonicity is the more potent.
• An increase in plasma osmolality of only 2% to 3% produces a strong desire to drink, whereas decreases in blood volume and pressure in the range of 10% to 15% are required to produce the same response.
• As already discussed, people have a genetically determined threshold for AVP secretion (i.e., a body fluid osmolality above which AVP secretion increases).
• Similarly, people have a genetically determined threshold for triggering the sensation of thirst. However, the thirst threshold is higher than the threshold for AVP secretion.
• On average, the threshold for AVP secretion is approximately 285 mOsm/kg H₂O, whereas the thirst threshold is approximately 295 mOsm/kg H₂O. Because of this difference, thirst is stimulated at a body fluid osmolality at which AVP secretion is already stimulated.
• The neural centers involved in regulating water intake (the thirst center) are located in the same region of the hypothalamus involved with regulating AVP secretion.
• However, it is not certain if the same cells serve both functions. Indeed, the thirst response, like the regulation of AVP secretion, occurs only in response to effective osmoles (for example., NaCl).
• Even less is known about the pathways involved in the thirst response to decreased blood volume or pressure, but it is believed that the pathways are the same as those involved in the volume- and pressure-related regulation of AVP secretion.
• Angiotensin II, acting on cells of the thirst center (subfornical organ), also evokes the sensation of thirst. Because angiotensin II levels are increased when blood volume and pressure are reduced, this effect of angiotensin II contributes to the homeostatic response that restores and maintains the body fluids at their normal volumes.
• The sensation of thirst is satisfied by the act of drinking even before sufficient water is absorbed from the gastrointestinal tract to correct the plasma osmolality.
• Oropharyngeal and upper gastrointestinal receptors appear to be involved in this response. However, relief of the thirst sensation by these receptors is short-lived, and thirst is completely satisfied only when the plasma osmolality or blood volume or pressure is corrected.
• It should be apparent that the AVP and thirst systems work in concert to maintain water balance. An increase in plasma osmolality evokes drinking and, through AVP action on the kidneys, the conservation of water.
• Conversely, when the plasma osmolality is decreased, thirst is suppressed and, in the absence of AVP, renal water excretion is enhanced.
• However, most of the time fluid intake is dictated by cultural factors and social situations, which is especially the case when thirst is not stimulated. In this situation, maintaining a normal body fluid osmolality relies solely on the ability of the kidneys to excrete water.
• How the kidney accomplishes this task is discussed in detail in the following sections of this chapter.

“Disorders of osmolality and water balance explained”

Renal Mechanisms For Dilution And Concentration Of The Urine

Under normal circumstances, the excretion of water is regulated separately from the excretion of solutes.

• For this separate regulation to occur, the kidneys must be able to excrete urine that is either hypoosmotic or hyperosmotic concerning the body fluids.
• This ability to excrete urine of varying osmolality in turn requires that solute be separated from water at some point along the nephron. As discussed, the reabsorption of solute in the proximal tubule results in the reabsorption of a proportional amount of water.
• Hence solute and water are not separated in this portion of the nephron. Moreover, this proportionality between proximal tubule water and solute reabsorption occurs regardless of whether the kidneys excrete dilute or concentrated urine.
• Thus the proximal tubule reabsorbs a large portion of the filtered solute and water but does not produce dilute or concentrated tubular fluid. The loop of Henle, in particular the thick ascending limb, is the major site where solute and water are separated.
• Thus the excretion of both dilute and concentrated urine requires normal function of the loop of Henle.

With adequate access to water, the thirst mechanism can prevent the development of hyperosmolality. Indeed, it is this mechanism that is responsible for the polydipsia seen in response to the polyuria of both central and nephrogenic diabetes insipidus.

“Role of osmolality regulation in diagnosing diseases”

• Water intake also is influenced by social and cultural factors. Thus persons ingest water even in the absence of the thirst sensation. Normally the kidneys can excrete this excess water because they can excrete up to 18 L/day of urine.
• However, in some instances, the volume of water ingested exceeds the kidneys’ capacity to excrete water, especially over short periods. When this situation occurs, the body fluids become hypoosmotic.
• An example of how water intake can exceed the capacity of the kidneys to excrete water is found in long-distance runners.
• A study of participants in the Boston Marathon found that hyponatremia developed in 13% of the runners during the race.

This finding reflected the practice of some runners of ingesting water, or other hypotonic drinks, during the race to remain “well hydrated.”

• In addition, water is produced from the metabolism of glycogen and triglycerides used as fuels by the exercising muscle.
• Because throughout the race they ingested and generated more water through metabolism than their kidneys were able to excrete, hyponatremia developed. In some racers, the hyponatremia was severe enough to elicit the neurologic symptoms described previously.
• Throughout the popular media, one can find articles urging us to drink eight 8-oz glasses of water a day (the 8 × 8 recommendation). Drinking this volume of water is said to provide innumerable health benefits.
• As a result, it seems that everyone now has a water bottle as his or her constant companion.
• Although ingesting this volume of water over a day (approximately 2 L) does not harm most persons, no scientific evidence exists to support the beneficial health claims ascribed to the 8 x 8 recommendation. t Indeed, most persons get adequate amounts of water through the foods they ingest and the fluids taken with those meals.
• The maximum amount of water that can be excreted by the kidneys depends on the amount of solute excreted, which in turn depends on food intake.

“How does dehydration affect osmolality?”

For example, with maximally dilute urine (urine osmolality [U_osm] = 50 mOsm/kg H₂O), the maximum urine output of 18 L/day is achieved only if the solute excretion rate is 900 mmol/day.

U_osm = Solute excretion/Volume excreted 50 mOsm/kg H₂O = 900 mmol/18 L

• If solute excretion is reduced, as commonly occurs in elderly people with reduced food intake, the maximum urine output decreases.
• For example, if solute excretion is only 400 mmol/day, a maximum urine output (at U_osm = 50 mOsm/kg H₂O) of only 8 L/day can be achieved. Thus persons with reduced food intake have a reduced capacity to excrete water.

The excretion of hypoosmotic urine is relatively easy to understand. The nephron simply must reabsorb solute from the tubular fluid and not allow water reabsorption to occur as well.

• The reabsorption of solute without concomitant water reabsorption occurs in some portions of the descending limb and along the entire ascending limb of Henle’s loop.
• Under appropriate conditions (i.e., in the absence of AVP), the distal tubule and collecting duct also dilute the tubular fluid.
• The excretion of hyperosmotic urine is more complex and thus more difficult to understand. This process in essence involves removing water from the tubular fluid without solute.

“Complications of overhydration and hyponatremia”

Because water movement is passive, driven by an osmotic gradient, the kidney must generate a hyperosmotic compartment that then reabsorbs water osmotically from the tubular fluid.

• The compartment in the kidney where this reabsorption occurs is the interstitial space of the renal medulla.
• It has long been recognized that Henle’s loop is associated with the kidneys’ ability to excrete hyperosmotic urine.
• Indeed, only birds and mammals can excrete hyperosmotic urine, and among vertebrates, only the avian and mammalian kidneys have loops of Henle.

Moreover, some animals, such as desert rodents, have extremely long loops of Henle and excrete urine with an osmolality that can exceed 5000 mOsm/kg H₂O.

• This extraordinary ability to concentrate the urine allows the animals to survive without the need to drink water because they obtain sufficient water in the food (for example., seeds) that they ingest.
• For more than 50 years our understanding of how the loop of Henle can generate a hyperosmotic environment within the renal medulla was focused on the process of countercurrent multiplication.
• By this process, solute (principally NaCl) is reabsorbed without water from the ascending limb of Henle’s loop into the surrounding medullary interstitium.

This reabsorption decreases the osmolality in the tubular fluid and raises the osmolality of the interstitium at this point.

• The increased osmolality of the interstitium then causes water to be reabsorbed from the descending limb of Henle’s loop, thus increasing the tubular fluid osmolality in this segment.
• Thus at any point along the loop of Henle, the fluid in the ascending limb has an osmolality less than fluid in the adjacent descending limb. This osmotic difference was termed the single effect.
• Because of the countercurrent flow of tubular fluid in the descending (fluid flowing into the medulla) and ascending (fluid flowing out of the medulla) limbs, this single effect could be multiplied.

“Techniques for monitoring osmolality levels”

The multiplication of this single effect results in an osmotic gradient within the medullary interstitium, where the tip of the papilla has an osmolality of 1200 mOsm/kg H₂O, compared with 300 mOsm/kg H₂O at the corticomedullary junction.

• Although it is simple in concept, it is now clear that countercurrent multiplication cannot fully explain the process by which the loop of Henle generates a hyperosmotic medullary interstitium.

Given our evolving understanding, specifically of the urine-concentrating mechanism, what follows is a simplified explanation that highlights several key concepts:

1. Urine is concentrated by the AVP-dependent reabsorption of water from the collecting duct.
2. Reabsorption of NaCl from the ascending limb of Henle’s loop generates a high [NaCl] in the medullary interstitium (up to 600 mmol/L at the tip of the papilla), which then drives water reabsorption from the collecting duct.
3. Urea accumulates in the medullary interstitium (up to 600 mmol/L), which allows the kidneys to excrete urine with the same high urea concentration. This phenomenon allows large amounts of urea to be excreted with relatively little water.

Summarizes the essential features of the mechanisms whereby the kidneys excrete either dilute or concentrated urine.

First, how the kidneys excrete dilute urine (water diuresis) when AVP levels are low or zero is considered. The following numbers refer to those encircled.

1. Fluid entering the descending thin limb of the loop of Henle from the proximal tubule is isosmotic concerning plasma.

• This state reflects the essentially isosmotic nature of the solute and water reabsorption in the proximal tubule. (Note: Water is reabsorbed from the segments of the proximal tubule via AQP-1).

2. Depending on the nephron type (i.e., short-looped nephrons versus long-looped nephrons, some water will be reabsorbed by the thin descending limb.

• Importantly, this water reabsorption is limited to the outer medulla and the outermost portion of the inner medulla.
• By con-fining water reabsorption to these outer portions of the medulla, less water is added to the deepest part of the inner medullary interstitial space, thus preserving the hyperosmolality of this region of the medulla.

3. In the inner medulla, the terminal portion of the descending thin limb and all of the thin ascending limb are impermeable to water.

• These same nephron segments express the Cl^– transporter ClC-K1, which mediates Cl^– reabsorption with Na⁺ following passively via the paracellular pathway.
• This passive reabsorption of NaCl without concomitant water reabsorption begins the process of diluting the tubular fluid.

“Pathophysiology of osmolality imbalances explained”

“Emerging research on osmolality regulation mechanisms”

4. The thick ascending limb of the loop of Henle also is impermeable to water and actively reabsorbs NaCl from the tubular fluid thereby diluting it further.

• Dilution occurs to such a degree that this segment often is referred to as the diluting segment of the kidney.
• Fluid leaving the thick ascending limb is hypoosmotic concerning plasma (approximately 150 mOsm/kg H₂O).

5. The distal tubule and cortical portion of the collecting duct actively reabsorb NaCl. In the absence of AVP, these segments are not permeable to water (i.e., AQP-2 is not present in the apical membrane of the cells).

• Thus when AVP is absent or present at low levels (i.e., decreased plasma osmolality), the osmolality of tubule fluid in these segments is reduced further because NaCl is reabsorbed without water.
• Under this condition, fluid leaving the cortical portion of the collecting duct is hypo-motif concerning plasma (approximately 50-100 mOsm/kg H₂O).

6. The medullary collecting duct actively reabsorbs NaCl. Even in the absence of AVP, this segment is slightly permeable to water, and some water is reabsorbed.

7. The urine has an osmolality as low as approximately 50 mOsm/kg H₂O and contains low concentrations of NaCl. The volume of urine excreted can be as much as 18 L/day or approximately 10% of the glomerular filtration rate (GFR).

• Next, how the kidneys excrete concentrated urine (antidiuresis) when plasma osmolality and plasma AVP levels are high is considered. The following numbers refer to those encircled.
• These steps are similar to those for the production of dilute urine. An important point in understanding how concentrated urine is produced is to recognize that while reabsorption of NaCl by the ascending thin and thick limbs of the loop of Henle dilutes the tubular fluid, the reabsorbed NaCl accumulates in the medullary interstitium and raises the osmolality of this compartment.
• The accumulation of NaCl in the medullary interstitium is crucial for the production of urine hyperosmotic to plasma because it provides the osmotic driving force for water reabsorption by the medullary collecting duct.
• As already noted, AVP stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop.
• This action is thought to maintain the medullary interstitial gradient at a time when water is being added to this compartment from the medullary collecting duct, which would tend to dissipate the gradient.

“Case studies on osmolality and water balance outcomes”

Because of NaCl reabsorption by the ascending limb of the loop of Henle, the fluid reaching the collecting duct is hypoosmotic concerning the surrounding interstitial fluid.

Thus an osmotic gradient is established across the collecting duct.

• In the presence of AVP, which increases the water permeability of the last half of the distal tubule and the collecting duct by increasing the number of AQP-2 water channels in the luminal membrane of the cells, water diffuses out of the tubule lumen, and the tubule fluid osmolality increases.
• This diffusion of water out of the lumen of the collecting duct begins the process of urine concentration.

The maximum osmolality that the fluid in the distal tubule and cortical portion of the collecting duct can attain is approximately 290 mOsm/kg H₂O (i.e., the same as plasma), which is the osmolality of the interstitial fluid and plasma within the cortex of the kidney.

• As the tubular fluid descends deeper into the medulla, water continues to be reabsorbed from the collecting duct, increasing the tubular fluid osmolality to 1200 mOsm/kg H₂O at the tip of the papilla.
• The urine produced when AVP levels are elevated has an osmolality of 1200 mOsm/kg H₂O and contains high concentrations of urea and other non-absorbed solutes. The urine volume under this condition can be as low as 0.5 L/day.
• Under most conditions, a relatively constant volume of tubular fluid is delivered to the AVP-sensitive portions of the nephron (late distal tubule and collecting duct).

Plasma AVP levels then determine the amount of water that is reabsorbed by these segments. When AVP levels are low, a relatively small volume of water is reabsorbed by these segments, and a large volume of hypoosmotic urine is excreted (up to 10% of the filtered water).

• When AVP levels are high, a large volume of water is reabsorbed by these same segments, and a small volume of hyperosmotic urine is excreted (<1% of filtered water).
• During antidiuresis, most of the water is reabsorbed in the distal tubule and cortical and outer medullary portions of the collecting duct.
• Thus a relatively small volume of fluid reaches the inner medullary collecting duct, where it is then reabsorbed.

This distribution of water reabsorption along the length of the collecting duct (i.e., cortex > outer medulla > inner medulla) allows for the maintenance of a hyperosmotic interstitial environment in the inner medulla by minimizing the amount of water entering this compartment.

Renal Mechanisms At The Cellular Level:

Water movement across the various segments of the nephron occurs through water channels.

• The proximal tubule and portions of some thin descending limbs of Henle’s loop are highly permeable to water, and these segments express high levels of AQP-1 in both the apical and basolateral membranes.
• The vasa recta also are highly permeable to water and express AQP-1. AQP-7 and AQP-8 also are expressed in the proximal tubule.
• As already discussed, AQP-2 is responsible for arginine vasopressin (AVP)-regulated water movement across the apical membrane of principal cells of the late distal tubule and collecting duct, and AQP-3 and AQP-4 are responsible for water movement across the basolateral membrane.
• Mice lacking the AQP-1 gene have been created. These mice have a urine-concentrating defect with increased urine output. Several persons have been found who also lack the normal AQP-1 gene.
• Interestingly, these persons do not have polyuria. However, when challenged by water deprivation, they can concentrate their urine to only approximately half of what is seen in a healthy person.

“Global prevalence of osmolality disorders”

Role Of Urea

As noted, a hyperosmotic renal medullary interstitium is critically important in concentrating the urine and provides the driving force for the reabsorption of water from the collecting duct.

• The principal solutes within the renal medullary interstitium are NaCl and urea, but the concentration of these solutes is not uniform throughout the medulla (i.e., a gradient exists from cortex to papilla).
• Other solutes also accumulate in the medulla (for example., ammonium [NH⁺₄] and K⁺), but the most abundant solutes are NaCl and urea. For simplicity, this discussion assumes that NaCl and urea are the only solutes.
• At the junction of the medulla with the cortex, the interstitial fluid has an osmolality of approximately 300 mOsm/kg H₂O, with virtually all osmoles attributable to NaCl. The concentrations of both NaCl and urea increase progressively with increasing depth into the medulla.

When maximally concentrated urine is excreted, the medullary interstitial fluid osmolality is approximately 1200 mOsm/kg H₂O at the papilla.

• Of this value, approximately 600 mOsm/ kg H₂O is attributed to NaCl, and 600 mOsm/kg H₂O is attributed to urea. As described later, NaCl is an effective osmole in the inner medulla and thus is responsible for driving water reabsorption from the medullary collecting duct. T
• The high urea concentration of the medullary interstitial fluid allows this solute to be excreted at a high concentration (600 mmol/L) in a small volume of urine, thus limiting the amount of water that otherwise would be needed to excrete the daily load of bread
• The medullary gradient for NaCl results from the accumulation of NaCl reabsorbed by the segments of Henle’s loop (see the previous discussion).
• Urea accumulation within the medullary interstitium is more complex and occurs most effectively when hyperosmotic urine is excreted (i.e., antidiuresis). When dilute urine is produced, especially over extended periods, the osmolality of the medullary interstitium declines.
• This reduced osmolality is almost entirely caused by a decrease in the concentration of urea. This decrease reflects washout by the vasa recta (discussed in a later section of this chapter) and diffusion of urea from the interstitium into the tubular fluid within the medullary portion of the collecting duct.

(Note: The cortical and outer medullary portions of the collecting have a low permeability to urea, whereas the inner medullary portion has a relatively high permeability because of the presence.)

• Urea is not synthesized in the kidney but is generated by the liver as a product of protein metabolism. It enters the tubular fluid via glomerular filtration.
• Approximately half of this filtered urea is reabsorbed by the proximal tubule. During antidiuresis, water reabsorption by the cortical and outer medullary portions of the collecting duct leads to an increase in the urea concentration of the tubular fluid.
• When this fluid reaches the portion of the inner medullary collecting duct that expresses UT-A1 and UT-A3, urea is reabsorbed.
• The reabsorption of urea is further enhanced by the high levels of AVP, which increase the expression of the UTs. Some of this reabsorbed urea is secreted into thin descending limbs of Henle’s loops via UT-A2, and some enter vasa recta via UT-B.

The urea that is secreted into the descending thin limbs of Henle’s loops is then trapped in the nephron until it again reaches the medullary collecting duct, where it can reenter the medullary interstitium.

• Thus urea recycles from the interstitium to the nephron and back into the interstitium. This process of recycling facilitates the accumulation of urea in the medullary interstitium, where it can attain a concentration at the tip of the papilla of 600 mmol/L.
• It is the high concentration of urea in the interstitial fluid that prevents the diffusion of urea out of the lumen of the inner medullary collecting duct into the interstitium, thereby facilitating urea excretion in the urine.
• As described, the hyperosmotic medulla is essential for concentrating the tubular fluid within the collecting duct.
• Because water reabsorption from the collecting duct is driven by the osmotic gradient established in the medullary interstitium, urine can never be more concentrated than that of the interstitial fluid in the papilla.
• Thus any condition that reduces the medullary interstitial osmolality impairs the ability of the kidneys to maximally concentrate the urine.

However, because the inner medullary collecting duct is highly permeable to urea, especially in the presence of AVP, urea cannot drive water reabsorption across this nephron segment (i.e., urea is an ineffective osmole).

• Instead, the urea in the tubular fluid and medullary interstitium equilibrate and a small volume of urine with a high concentration of urea is excreted.
• It is the medullary interstitial NaCl concentration that is responsible for reabsorbing water from the inner medullary collecting duct and thereby concentrating the nonurea solutes (for example., NH⁺ salts, K⁺ salts, and creatinine) in the urine.

At The Cellular Level

The expression of the urea transporter (UT­A1) in the inner medullary collecting duct is increased by arginine vasopressin (AVP) via a cyclic adenosine monophosphate–mediated mechanism. UT­A1 expression also is increased by hyperosmolality.

• This effect is mediated by changes in intracellular Ca++ and protein kinase C activity. Thus the effects of AVP and hyperosmolality are separate and additive.
• The expression of UT­A3 and UT­A2 also is increased by AVP. Knockout mice have been created that lack the UT­A1/UT­A3 collecting duct transporters, the UT­A2 thin descending limb transporter, or the UT­B vasa recta transporter.
• All of these animals have some degree of impairment of urinary concentration. Humans with genetic loss of UT­B exhibit a similar urinary concentrating defect as the knockout mouse model.

Vasa Recta Function

The vasa recta, the capillary networks that supply blood to the medulla, are highly permeable to solute and water. As with the loop of Henle, the vasa recta form a parallel set of hairpin loops within the medulla.

• Not only do the vasa recta bring nutrients and oxygen to the medullary nephron segments but, more importantly, they also remove the water and solute that is continuously added to the medullary interstitium by these nephron segments.
• The ability of the vasa recta to maintain the medullary interstitial gradient is flow-dependent. A substantial increase in vasa recta blood flow dissipates the medullary gradient. Alternatively, decreased blood flow reduces oxygen delivery to the nephron segments within the medulla.
• Because the transport of salt and other solutes requires oxygen and adenosine triphosphate, reduced medullary blood flow decreases salt and solute transport by nephron segments in the medulla. As a result, the medullary interstitial osmotic gradient cannot be maintained, which also reduces the ability to concentrate the urine.

Assessment Of Renal Diluting And Concentrating Ability

Assessment of renal water handling includes measurements of urine osmolality and the volume of urine excreted. The range of urine osmolality is from 50 to 1200 mOsm/kg H₂O.

• The corresponding range in urine volume is 18 to as little as 0.5 L/day. These ranges are not fixed, but they vary from person to person and, as noted previously, depend on the amount of water ingested and lost from nonrenal routes, as well as the amount of solute excreted.
• As emphasized in this chapter, the ability of the kidneys to dilute or concentrate the urine requires the separation of solute and water.
• This separation of solute and water in essence generates a volume of water that is “free of solute.” When the urine is dilute, solute-free water is excreted from the body.
• When the urine is concentrated, solute-free water is returned to the body (i.e., conserved).
• The concept of free water clearance (CH₂O) provides a way to calculate the amount of solute-free water generated by the kidneys, either when dilute urine is excreted or when concentrated urine is formed.
• As its name denotes, CH₂O is directly derived from the concept of renal clearance discussed.

“Complications of ignoring osmolality issues”

To calculate CH₂O, the clearance of total solute by the kidneys must be calculated. This clearance of total solute (i.e., osmoles, whether effective or ineffective) from plasma by the kidneys is termed the osmolar clearance (C_osm) and can be calculated as follows:

⇒ \(\mathrm{C}_{\mathrm{OSM}}=\frac{\mathrm{U}_{\mathrm{OSM}} \times \dot{\mathrm{V}}}{\mathrm{P}_{\mathrm{OSM}}}[latex]

where U_osm is the urine osmolality, V is the urine flow rate, and P_osm is the osmolality of plasma. Cosm has units of volume/unit time. CH₂O is then calculated as follows:

⇒ [latex]\mathrm{C}_{\mathrm{H}_2 \mathrm{O}}=\dot{\mathrm{V}}-\mathrm{C}_{\mathrm{osm}}\)

By rearranging equations 5-3; it should be apparent that

⇒ \(\dot{\mathrm{V}}=\mathrm{C}_{\mathrm{H}_2 \mathrm{O}}+\mathrm{C}_{\mathrm{osm}}\)

In other words, it is possible to partition the total urine output (V) into two hypothetical components. One component contains all the urine solutes and has an osmolality equal to that of plasma (i.e., U_osm = P_osm).

• This volume is defined by Cosm and represents a volume from which there has been no separation of solute and water. The second component is a volume of solute-free water (i.e., CH₂O).
• When dilute urine is produced, the value of CH₂O is positive, indicating that solute-free water is excreted from the body. When concentrated urine is produced, the value of CH₂O is negative, indicating that solute-free water is retained in the body.
• By convention, negative CH₂O values are expressed as T^CH₂O (tubular conservation of water).
• Calculating ^CH₂O and T^CH₂O can provide important information about the function of the portions of the nephron involved in producing dilute and concentrated urine.

Whether the kidneys excrete or reabsorb free water depends on the presence of AVP. When AVP is absent or AVP levels are low, solute-free water is excreted. When AVP levels are high, solute-free water is reabsorbed.

The following factors are necessary for the kidneys to excrete a maximal amount of solute-free water (CH₂O):

1. AVP must be absent. Without AVP, the collecting duct does not reabsorb a significant amount of water.
2. The tubular structures that separate solute from water (i.e., dilute the luminal fluid) must function normally. In the absence of AVP, the following nephron segments can dilute the luminal fluid:
   • Thin ascending limb of Henle’s loop
   • Thick ascending limb of Henle’s loop
   • Distal tubule
   • Collecting duct
3. Because of its high transport rate, the thick ascending limb is quantitatively the most important of these segments involved in the separation of solute and water.
   • An adequate amount of tubular fluid must be delivered to the aforementioned nephron sites for maximal separation of solute and water.
   • Factors that reduce delivery (for example., decreased GFR or enhanced proximal tubule reabsorption) impair the kidneys’ ability to excrete solute-free water.

Similar requirements also apply to the conservation of water by the kidneys (TCH₂O). For the kidneys to conserve water maximally, the following conditions must exist:

1. An adequate amount of tubular fluid must be delivered to the nephron segments in which separation of solute from water occurs. The important segment in the separation of solute and water is the thick ascending limb of Henle’s loop. Delivery of tubular fluid to Henle’s loop depends on GFR and proximal tubule reabsorption.
2. Reabsorption of NaCl by the nephron segments must be normal; again, the most important segment is the thick ascending limb of Henle’s loop.
3. A hyperosmotic medullary interstitium must be present. The interstitial fluid osmolality is maintained by NaCl reabsorption by Henle’s loop (con-ditions 1 and 2) and by effective accumulation of urea. Urea accumulation in turn depends on ade-quate dietary protein intake.
4. Maximum levels of AVP must be present and the collecting duct must respond normally to AVP.

The concept of free-water clearance as just described does not distinguish between effective and ineffective osmoles, either in the plasma or in the urine.

However, urea, which can account for half of the total urine osmoles, is not an effective osmole when the movement of water between intracellular fluid and extracellular fluid is considered.

Accordingly, when one wants to understand how the handling of water by the kidneys contributes to the maintenance of whole-body water balance, it is more appropriate to consider only the solutes that are effective osmoles. For plasma (i.e., extracellular fluid), the effective osmoles are Na⁺ and its attendant anions. For urine, they are the nonurea solutes.

The importance of using effective osmoles in determining the impact of renal water handling on whole-body water balance (i.e., body fluid osmolality) is illustrated by the following example.

A patient has an elevated plasma [urea], and his plasma [Na⁺] also is increased to 150 mEq/L. His total plasma osmolality (including urea) is 320 mOsm/kg H₂O, but his effective plasma osmolality (calculated as 2 x plasma [Na⁺]) is only 300 mOsm/kg H₂O.

His urine osmolality is 600 mOsm/kg H₂O, with 300 mOsm/ kg H₂O related to urea and 300 mOsm/kg H₂O related to nonurea solutes. His urinary flow rate is 3 L/day.

According to equations 5-2 and 5-3, his total osmolar clearance (C_osm) and free-water clearance (C_H2O) are as follows:

⇒ \(\mathrm{C}_{\mathrm{oSM}}=\frac{600 \mathrm{mOsm} / \mathrm{kg} \mathrm{H}_2 \mathrm{O} \times 3 \mathrm{~L} / \text { day }}{320 \mathrm{mOsm} / \mathrm{kg} \mathrm{H}_2 \mathrm{O}}=5.6 \mathrm{~L} / \text { day }\)

⇒ \(\mathrm{C}_{\mathrm{H}_2 \mathrm{O}}=3 \mathrm{~L} / \text { day }-5.6 \mathrm{~L} / \text { day }=-2.6 \mathrm{~L} / \text { day }\left(\mathrm{T}_{\mathrm{H}_2 \mathrm{O}}^{\mathrm{C}}\right)\)

Thus it appears that the kidneys are conserving 2.6 L/day of solute-free water, which would be an appropriate response to correct the elevated plasma osmolality.

However, when C_osm and C_H2O are analyzed from the perspective of effective osmoles, the following results are obtained:

⇒ \(\text { Cosm }=\frac{300 \mathrm{mOsm} / \mathrm{kg} \mathrm{H}_2 \mathrm{O} \times 3 \mathrm{~L} / \text { day }}{300 \mathrm{mOsm} / \mathrm{kg} \mathrm{H}_2 \mathrm{O}}=3 \mathrm{~L} / \text { day }\)

⇒ \(\mathrm{C}_{\mathrm{H}_2 \mathrm{O}}=3 \mathrm{~L} / \text { day }-3 \mathrm{~L} / \text { day }=0 \mathrm{~L} / \text { day }\)

When viewed from the more appropriate perspective of effective osmoles, it thus is apparent that the kidneys are not reabsorbing solute-free water and the patient’s kidneys are not correcting the hyperosmolality.

The post Regulation Of Body Fluid Osmolality Regulation Of Water Balance appeared first on BDS Notes.

“What is the regulation of extracellular fluid volume?”

The major solutes of the extracellular fluid (ECF) are the salts of Na⁺. Of these, sodium chloride (NaCl) is the most abundant.

• Because NaCl is also the major determinant of ECF osmolality, alterations in Na⁺ balance commonly are assumed to disturb ECF osmolality.
• However, under normal circumstances, this is not the case because the arginine vasopressin (AVP) and thirst systems maintain body fluid osmolality within a very narrow range.
• For example, the addition of NaCl to the ECF (without water) increases the Na+ concentration and osmolality of this compartment (intracellular fluid osmolality also increases because of osmotic equilibration with the ECF).

“Understanding the role of NaCl in fluid balance”

This increase in osmolality in turn stimulates thirst and the release of AVP from the posterior pituitary.

• The increased ingestion of water in response to thirst, together with the AVP-induced decrease in water excretion by the kidneys (so-called antidiuresis), quickly restores ECF osmolality to normal.
• However, the volume of the ECF increases in proportion to the amount of water ingested, which in turn depends on the amount of NaCl added to the ECF.
• Thus in the new steady state, the addition of NaCl to the ECF is equivalent to adding an isosmotic solution, and the volume of this compartment increases. Conversely, a decrease in the NaCl content of the ECF lowers the volume of this compartment.

The kidneys are the major route for the excretion of NaCl from the body. Only about 10% of the Na⁺ lost from the body each day is lost by nonrenal routes (for example., in perspiration and feces).

“How does the body regulate ECF volume and NaCl balance?”

Thus the kidneys are critically important in regulating the volume of the ECF.

• Under normal conditions, the kidneys keep the volume of the ECF constant by adjusting the excretion of NaCl to match the amount ingested in the diet.
• If ingestion exceeds excretion, ECF volume increases above normal, whereas the opposite occurs if excretion exceeds ingestion.
• It has been observed that the kidneys excrete sodium chloride (NaCl) more quickly when the NaCl is administered orally versus by an intravenous infusion.

This observation has led to the search for factors within the gastrointestinal tract that might modulate the renal excretion of NaCl. Indeed, neuroendocrine cells that produce the peptide hormones uroguanylin and guanylin in response to NaCl ingestion have been identified in the intestine.

• These hormones increase NaCl and water excretion by the kidneys (uroguanylin > guanylin) by inhibiting Na⁺ reabsorption in both the proximal tubule and collecting duct.
• Interestingly, the kidneys also produce uroguanylin and guanylin, suggesting that they also might play a paracrine role in the intrarenal regulation of NaCl excretion.
• The potential importance of these peptides in regulating renal NaCl excretion is seen in mice lacking the uroguanylin gene. These mice have a blunted natriuretic response to an oral NaCl load, and they also have increased blood pressure.

The typical diet contains approximately 140 mEq/ day of Na⁺ (8 g of NaCl), and thus daily Na⁺ excretion is also about 140 mEq/day. However, the kidneys can vary the excretion of Na⁺ over a wide range.

• Excretion rates as low as 10 mEq/day can be attained when persons are placed on a low-salt diet. Conversely, the kidneys can increase their excretion rate to more than 1000 mEq/day when challenged by the ingestion of a high-salt diet.
• These changes in Na+ excretion can occur with only modest changes in the ECF volume and steady-state Na⁺ content of the body.
• The response of the kidneys to abrupt changes in NaCl intake typically takes several hours to several days, depending on the magnitude of the change. During this transition period, the intake and excretion of Na⁺ are not matched as they are in the steady state.

“Importance of maintaining extracellular fluid volume”

Thus the individual experiences either positive Na⁺ balance (intake > excretion) or negative Na⁺ balance (intake < excretion). However, by the end of the transition period, a new steady state is established, and intake once again equals excretion.

• Provided that the AVP and thirst systems are intact and normal, alterations in Na+ balance change the volume, but not the Na⁺ concentration, of the ECF. Changes in ECF volume can be monitored by measuring body weight because 1 L of ECF equals 1 kg of body weight.
• In this chapter, the physiology of the receptors that monitor ECF volume is reviewed and the various signals that act on the kidneys to regulate NaCl excretion and thereby ECF volume are explained.
• In addition, the responses of the various portions of the nephron to these signals are considered. Finally, the pathophysiologic mechanisms involved in the formation of edema are presented, with emphasis on the role of NaCl handling by the kidneys.

Concept Of Effective Circulating Volume

As described, the ECF is subdivided into two compartments: blood plasma and interstitial fluid. Plasma volume is a determinant of vascular volume and thus blood pressure and cardiac output.

• The maintenance of Na⁺ balance, and thus ECF volume, involves a complex system of sensors and effector signals that act primarily on the kidneys to regulate the excretion of NaCl.
• As can be appreciated from the dependence of vascular volume, blood pressure, and cardiac output on ECF volume, this complex system is designed to ensure adequate tissue perfusion.
• Because the primary sensors of this system are located in the large vessels of the vascular system, changes in vascular volume, blood pressure, and cardiac output are the principal factors regulating renal NaCl excretion (described later in this chapter).

In a healthy person, changes in ECF volume result in parallel changes in vascular volume, blood pressure, and cardiac output. Thus a decrease in ECF volume, a situation termed volume contraction, results in reduced vascular volume, blood pressure, and cardiac output.

• Conversely, an increase in ECF volume, a situation termed volume expansion, results in increased vascular volume, blood pressure, and cardiac output.
• The degree to which these cardiovascular parameters change depends on the degree of volume contraction or expansion and the effectiveness of cardiovascular reflex mechanisms.
• When a person is in a negative Na⁺ balance, ECF volume is decreased and renal NaCl excretion is reduced. Conversely, with a positive Na⁺ balance, an increase in ECF volume occurs, which results in enhanced renal NaCl excretion (i.e., natriuresis).

However, in some pathologic conditions (for example., congestive heart failure and hepatic cirrhosis), the renal excretion of NaCl is not reflective of the ECF volume.

• In both of these situations, the volume of the ECF is increased. However, instead of increased renal NaCl excretion, as would be expected, a reduction in the renal excretion of NaCl occurs.
• To explain renal Na+ handling in these situations, it is necessary to understand the concept of effective circulating volume (ECV). Unlike the ECF, the ECV is not a measurable and distinct body fluid compartment.
• The ECV refers to the portion of the ECF that is contained within the vascular system and is “effectively” perfusing the tissues (effective blood volume is another commonly used term).

“Common mechanisms of NaCl balance regulation explained”

More specifically, the ECV reflects the perfusion of those portions of the vascular system that contain the volume sensors (described later in this chapter).

• In healthy persons, ECV varies directly with the volume of the ECF and, in particular, the volume of the vascular system (arterial and venous), the arterial blood pressure, and cardiac output.
• However, as noted, this is not the case in certain pathologic conditions. In the remaining sections of this chapter, the relationship between ECF volume and renal NaCl excretion in healthy adults, where changes in ECV and ECF volume occur in parallel, is examined.
• Patients with congestive heart failure frequently have an increase in the volume of the extracellular fluid (ECF), which is manifested as an accumulation of fluid in the lungs (pulmonary edema) and peripheral tissues (peripheral edema).

This excess fluid is the result of sodium chloride (NaCl) and water retention by the kidneys. The kidneys’ response (i.e., retention of NaCl and water) appears paradoxical because the ECF volume is increased.

• However, because of poor cardiac performance, perfusion of the portions of the vascular system that contain the volume sensors is reduced (i.e., decreased effective circulating volume).
• Therefore the volume sensors misinterpret these signals as indicative of ECF volume contraction and respond by increasing NaCl and water retention by the kidneys, thereby exacerbating a vicious cycle of impaired cardiac function and increased NaCl and water reabsorption.
• Large volumes of fluid accumulate in the peritoneal cavity of patients with advanced hepatic cirrhosis. This fluid, called ascites, is a component of the ECF and results from NaCl and water retention by the kidneys.

Again, the response of the kidneys in this situation seems paradoxical if only ECF volume is considered.

• With advanced hepatic cirrhosis, blood pools in the splanchnic circulation (i.e., the damaged liver impedes the drainage of blood from the splanchnic circulation by the portal vein).
• Thus volume and pressure are reduced in the portions of the vascular system where the volume sensors are found and, as in the case of congestive heart failure, the volume sensors interpret reduced effective circulating volume as decreased ECF volume and respond accordingly.
• Hence the kidneys respond as they normally would to ECF volume contraction, resulting in NaCl and water retention and an increase in ECF volume, which results in the accumulation of ascites fluid.

“Role of aldosterone in regulating NaCl balance”

Volume Sensing Systems

The ECF volume (or ECV) is monitored by multiple sensors. A number of the sensors are located in the vascular system, and they monitor its fullness and pressure.

• These receptors typically are called volume receptors; because they respond to pressure-induced stretch of the walls of the receptor (for example., blood vessels or cardiac atria), they also are referred to as baroreceptors.
• The sensors within the liver and central nervous system (CNS) are less well understood and do not seem to be as important as the vascular sensors in monitoring the ECF volume.

Volume Sensors In The Low-Pressure Cardiopulmonary Circuit:

Volume sensors (i.e., baroreceptors), which are located within the walls of the cardiac atria, right ventricle, and large pulmonary vessels, respond to the distention of these structures.

• Because the low-pressure venous side of the circulatory system has high compliance, these sensors respond mainly to the “fullness” of the vascular system.
• These baroreceptors send signals to the brainstem through afferent fibers in the glossopharyngeal and vagus nerves. The activity of these sensors modulates both sympathetic nerve outflow and AVP secretion.
• For example, a decrease in the filling of the pulmonary vessels and cardiac atria increases sympathetic nerve activity and stimulates AVP secretion. Conversely, distention of these structures decreases sympathetic nerve activity.

In general, 5% to 10% changes in blood volume and pressure are necessary to evoke a response.

• The cardiac atria possess an additional mechanism related to the control of renal NaCl excretion. The myocytes of the atria synthesize and store a peptide hormone.
• This hormone, termed atrial natriuretic peptide (ANP), is released when the atria are distended, which, by mechanisms outlined later in this chapter, reduces blood pressure and increases the excretion of NaCl and water by the kidneys.
• The ventricles of the heart also produce a natriuretic peptide termed brain natriuretic peptide (BNP), so named because it was first isolated from the brain. Like ANP, BNP is released from the ventricular myocytes by distension of the ventricles. Its actions are similar to those of ANP.

“How does ADH affect extracellular fluid volume?”

Volume Sensors In The High-Pressure Arterial Circuit:

Baroreceptors also are present in the arterial side of the circulatory system; they are located in the wall of the aortic arch, carotid sinus, and afferent arterioles of the kidneys.

• The aortic arch and carotid barorecep- tors send input to the brainstem through afferent fibers in the glossopharyngeal and vagus nerves. The response to this input alters sympathetic outflow and AVP secretion.
• Thus a decrease in blood pressure increases sympathetic nerve activity and AVP secretion. An increase in pressure tends to reduce sympathetic nerve activity (and activate parasympathetic nerve activity).
• The sensitivity of the high-pressure baroreceptors is similar to that in the low-pressure side of the vascular system; 5% to 10% changes in pressure are needed to evoke a response.

The juxtaglomerular apparatus of the kidneys, particularly the afferent arteriole, responds directly to changes in pressure. If perfusion pressure in the afferent arteriole is reduced, renin is released from the myocytes.

• Renin secretion is suppressed when perfusion pressure is increased. As described later in this chapter, renin determines blood levels of angiotensin II and aldosterone, both of which play an important role in regulating renal NaCl excretion.
• Of the two classes of baroreceptors, those on the high-pressure side of the vascular system appear to be more important in influencing sympathetic tone and AVP secretion.
• For example, patients with congestive heart failure often have an increased vascular volume with dilation of the atria and ventricles, which would be expected to decrease sympathetic tone and inhibit AVP secretion via the low-pressure baroreceptors.

Constriction of a renal artery by an atherosclerotic plaque, for example, reduces perfusion pressure to that kidney.

• This reduced perfusion pressure is sensed by the afferent arteriole of the juxtaglomerular apparatus and results in the secretion of renin.
• The elevated renin levels increase the production of angiotensin II, which in turn increases systemic blood pressure by its vasoconstrictor effect on arterioles throughout the vascular system.
• The increased systemic blood pressure is sensed by the juxtaglomerular apparatus of the contralateral kidney (i.e., the kidney without stenosis of its renal artery), and renin secretion from that kidney is suppressed.

“Impact of renin-angiotensin-aldosterone system (RAAS) on ECF volume”

In addition, the high levels of angiotensin II act to inhibit renin secretion by the contralateral kidney (negative feedback).

• The treatment of patients with constricted renal arteries includes surgical repair of the stenotic artery, administration of angiotensin 2 receptor blockers, or administration of an inhibitor of angiotensin-converting enzyme.
• The angiotensin-converting enzyme inhibitor blocks the conversion of angiotensin 1 to angiotensin 2.
• However, the sympathetic tone often is increased and AVP secretion often is stimulated in these patients (the renin-angiotensin-aldosterone system also is activated).
• This phenomenon reflects the activation of baroreceptors in the high-pressure arterial circuit in response to reduced blood pressure and cardiac out-put secondary to the failing heart (i.e., the high-pres-sure baroreceptors detect a reduced ECV and misinterpret this signal as indicative of reduced ECF volume).

Hepatic Sensors:

The liver also contains volume sensors that can modulate renal NaCl excretion, although they are not as important as the vascular sensors.

• One type of hepatic sensor responds to pressure within the hepatic vasculature and therefore functions in a manner similar to the baroreceptors in the low- and high-pressure vascular circuits.
• A second type of sensor also appears to exist in the liver. This sensor responds to [Na⁺] of the portal blood entering the liver.
• Afferent signals from both types of sensors are sent to the same area of the brainstem where afferent fibers from both the low- and high-pressure circuit baroreceptors converge.
• Increased pressure within the hepatic vasculature or an increase in portal blood [Na⁺] results in a decrease in efferent sympathetic nerve activity.

As described later in this chapter, this decreased sympathetic nerve activity leads to an increase in renal NaCl excretion.

Central Nervous System Na⁺ Sensors:

As with the hepatic sensors, the CNS sensors do not appear to be as important as the vascular sensors in monitoring the ECF volume and controlling renal NaCl excretion.

• Nevertheless, alterations in the [Na⁺] of blood carried to the brain in the carotid arteries or the [Na⁺] of the cerebrospinal fluid modulate renal NaCl excretion.
• For example, if the [Na⁺] in either the carotid artery blood or the cerebrospinal fluid is increased, a decrease in renal sympathetic nerve activity occurs, which in turn leads to an increase in renal NaCl excretion.
• The hypothalamus appears to be the site where these sensors are located. Angiotensin II and natriuretic peptides are generated in the hypothalamus.

These locally generated signals, together with systemically generated angiotensin II and natriuretic peptides, appear to play a role in modulating the CNS Na⁺-sensing system.

• Of the volume and Na+ sensors just described, those located in the vascular system are better understood. Moreover, their function in health and disease explains quite effectively the regulation of renal NaCl excretion.
• Therefore the remainder of this chapter focuses on the vascular volume sensors (i.e., baroreceptors) and their role in regulating renal NaCl excretion.

“Biomechanics of sodium reabsorption in the nephron”

Volume Sensor Signals:

When the vascular volume sensors have detected a change in ECV, which under normal conditions reflects ECF volume, they send signals to the kidneys, which result in appropriate adjustments in NaCl and water excretion.

• Accordingly, when the ECF volume is expanded, renal NaCl and water excretion are increased.
• Conversely, when the ECF volume is concentrated, renal NaCl and water excretion are reduced.
• The signals involved in coupling the volume sensors to the kidneys are both neural and hormonal. These signals are summarized, as are their effects on renal NaCl and water excretion.

Renal Sympathetic Nerves:

As described, sympathetic nerve fibers innervate the afferent and efferent arterioles of the glomerulus, as well as the nephron cells.

With negative Na⁺ balance (i.e., ECF volume contraction), baroreceptors in both the low- and high-pressure vascular circuits stimulate the sympathetic input to the kidneys.

This stimulation has the following effects:

The afferent and efferent arterioles constrict in response to a-adrenergic stimulation.

• This vaso-constriction predominantly affects the afferent arteriole, effectively reducing hydrostatic pressure within the glomerular capillary lumen and decreasing glomerular filtration.
• The resulting reduction in the glomerular filtration rate (GFR) reduces the filtered load of Na⁺ to the nephrons.
• Renin secretion is stimulated by the cells of the afferent arterioles in response to p-adrenergic receptor stimulation. As described later, renin ultimately increases the circulating levels of angiotensin II and aldosterone.

NaCl reabsorption along the nephron is directly stimulated by a-adrenergic stimulation, effectively reducing the fraction of filtered Na⁺ that is ultimately excreted.

• Quantitatively, the most important segment influenced by sympathetic nerve activity is the proximal tubule.
• As a result of these combined actions, increased renal sympathetic nerve activity decreases net NaCl excretion, an adaptive response that works to restore ECF volume to normal, which is a state termed euvolemia.
• With positive Na⁺ balance (i.e., ECF vol-ume expansion), renal sympathetic nerve activity is reduced, which generally reverses the effects just described.

Volume Sensing Systems At The Cellular Level:

A new “renal hormone” has been discovered recently, a flavin adenine dinucleotide-dependent amine oxidase named renalase.

• Renalase is similar in structure to monoamine oxidase and breaks down catechol amines (for example., epinephrine and norepinephrine).
• Several tissues (for example., skeletal muscle, heart, and small intestine) express renalase, but the kidneys secrete the enzyme into the circulation.

Because persons with chronic renal failure have very low levels of renalase in their plasma, the kidney is probably the primary source of the circulating enzyme.

• In experimental animals, infusion of renalase decreases blood pressure and heart contractility.
• Although the precise role of renalase in cardiovascular function and blood pressure regulation is not known, it may be important in modulating the effects of the sympathetic nervous system and especially the effects of the sympathetic nerves on the kidney.

“Steps in restoring NaCl balance during dehydration”

Renin-Angiotensin-Aldosterone System

Cells in the afferent arterioles (juxtaglomerular cells) are the site of synthesis, storage, and release of the proteolytic enzyme renin. Three factors are important in stimulating renin secretion:

1. Perfusion pressure. When perfusion pressure to the kidneys is reduced, renin secretion by the afferent arteriole is stimulated. Conversely, an increase in perfusion pressure inhibits renin release by the afferent arteriole.
2. Sympathetic nerve activity. Activation of the sympathetic nerve fibers that innervate the afferent arterioles increases renin secretion via P-adrenergic receptor stimulation. Renin secretion is decreased as renal sympathetic nerve activity is decreased.
3. Delivery of NaCl to the macula densa. Delivery of NaCl to the macula densa regulates the GFR by a process termed tubuloglomerular feedback.
   • In addition, the macula densa plays a role in renin secretion. When NaCl delivery to the macula densa is decreased, renin secretion is enhanced. Conversely, an increase in NaCl delivery inhibits renin secretion.
   • It is likely that macula densa-mediated renin secretion helps to maintain systemic arterial pressure under conditions of a reduced intravascular volume.
   • For example, when intravascular volume is reduced, perfusion of body tissues (including the kidneys) decreases, which in turn decreases the GFR and the filtered amount of NaCl.
   • The reduced delivery of NaCl to the macula densa then stimulates renin secretion, which acts through angiotensin II (a potent vasoconstrictor) to increase blood pressure and thereby maintain tissue perfusion.

Although many tissues express renin (for example., brain, heart, and adrenal gland tissues), the primary source of circulating renin is the kidneys. Renin is secreted by juxtaglomerular cells located in the afferent arteriole.

• At the cellular level, renin secretion is mediated by the fusion of renin-containing granules with the luminal membrane of the cell.
• This process is stimulated by a decrease in intracellular [Ca⁺⁺], a response opposite to that of most secretory cells where secretion is normally stimulated by an increase in intracellular [Ca⁺⁺].
• Renin release is also stimulated by an increase in intracellular cyclic adenosine monophosphate levels.

Thus anything that increases intracellular [Ca⁺⁺] inhibits renin secretion, which includes stretch of the afferent arteriole (myogenic control of renin secretion), angiotensin 2 (feedback inhibition), and endo- thelin.

• Conversely, anything that increases intracellular cyclic adenosine monophosphate stimulates renin secretion, which includes norepinephrine acting through p-adrenergic receptors and prostaglandin E₂.
• Increases in intracellular cyclic guanosine monophosphate have been shown to stimulate renin secretion in some situations and inhibit secretion in others.
• Notably, two substances that increase intracellular cyclic guanosine monophosphate are natriuretic peptides and nitric oxide.
• Nitric oxide stimulates renin secretion, whereas atrial natriuretic peptide and brain natriuretic peptide are inhibitory.

The control of renin secretion by the macula densa may involve paracrine factors such as prostaglandin E₂ (which stimulates renin secretion when NaCl delivery to the macula densa is decreased) and adenosine (which inhibits renin secretion when NaCl delivery to the macular densa is increased).

“Mechanisms of sodium reabsorption in the nephron”

Summarizes the essential components of the renin-angiotensin-aldosterone system. Renin alone does not have a physiological function; it functions as a proteolytic enzyme.

• Its principal substrate is a circulating protein, angiotensinogen, which is produced by the liver. Angiotensinogen is cleaved by renin to yield a 10-amino-acid peptide, angiotensin 1.
• Angiotensin 1 also has no known physiological function, and it is further cleaved to an 8-amino-acid peptide, angiotensin 2, by a converting enzyme (angiotensin-converting enzyme [ACE]) found on the surface of vascular endothelial cells.

1. Pulmonary and renal endothelial cells are important sites for the bioconversion of angiotensin 1 to angiotensin 2. ACE also degrades bradykinin, a potent vasodilator. Angiotensin 2 has several important physiologic functions, including:
2. Stimulation of aldosterone secretion by the adrenal cortex
3. Arteriolar vasoconstriction, which increases blood pressure
4. Stimulation of AVP secretion and thirst
5. Enhancement of NaCl reabsorption by the proximal tubule, thick ascending limb of Henle’s loop, the distal tubule, and even the collecting duct; of these segments, the effect on the proximal tubule is quantitatively the largest

Angiotensin 2 is an important secretagogue for aldosterone. An increase in the plasma K⁺ concentration is the other important stimulus for aldosterone secretion.

• Aldosterone is a steroid hormone produced by the glomerulosa cells of the adrenal cortex. Aldosterone acts in a number of ways on the kidneys.
• With regard to the regulation of the ECF volume, aldosterone reduces NaCl excretion by stimulating its reabsorption by the thick ascending limb of the loop of Henle, portions of the distal tubule, and the collecting duct.
• (The portions of the distal tubule that functionally respond to aldosterone together with the collecting duct are referred to as the aldosterone-sensitive distal nephron [ASDN].)

The effect of aldosterone on renal NaCl excretion depends mainly on its ability to stimulate Na+ reabsorption in the ASDN.

• Aldosterone has many cellular actions in cells of the ASDN.
• Notably, it increases the abundance of the apical membrane Na⁺– Cl^– symporter in the cells of the distal tubule (DCT2 segment; see previous
• At the Cellular Level box) and the abundance of the epithelial Na+ channel in the apical membrane of principal cells in the late portion of the distal tubule and collecting duct.

Volume Sensing System At The Cellular Level:

The distal tubule can be divided into three distinct segments based on the presence of specific membrane transporters.

• The first segment after the macula densa (DCT1) expresses a Na⁺-Cl^– symporter, which is specifically inhibited by the thiazide class of diuretics.
• The next segment (DCT2) expresses the Na⁺-Cl^– symporter and the epithelial Na⁺ channel. The last segment of the distal tubule (connecting tubule), like the collecting duct, expresses only the epithelial Na+ channel.
• Aldosterone selectivity and sensitivity are conferred by the presence of mineralocorticoid receptors, as well as the presence of the enzyme 11 β-hydroxysteroid dehydrogenase 2 (11β-HSD2).

Because the mineralocorticoid receptor also binds glucocorticoids, 11β- HSD2 is required for aldosterone specificity because it metabolizes glucocorticoids and thus prevents them from binding to the mineralocorticoid receptor.

• The mineralocorticoid receptor is found throughout the distal tubule and collecting duct. However, 11β- HSD2 is only found in the DCT2, the connecting tubule, and the collecting duct.
• Thus the aldosterone-sensitive distal nephron consists of the DCT2 and connecting tubule (collectively termed the late distal tubule) and the collecting duct. Accordingly, the DCT1 segment is referred to as the early distal tubule.
• By this action, Na⁺ entry into the cells across the apical membrane is increased. Extrusion of Na+ from the cell across the basolateral membrane occurs via the Na⁺-K⁺-adenos- ine triphosphatase (ATPase) pump, the abundance of which is also increased by aldosterone.

Thus aldosterone increases net reabsorption of Na+ from the tubular fluid by ASDN segments, and reduced levels of aldosterone decrease the amount of Na+ reabsorbed by these segments.

• As noted, aldosterone also enhances Na⁺ reabsorption by cells of the thick ascending limb of the loop of Henle.
• This action probably reflects the increased entry of Na⁺ into the cell across the apical membrane (probably by the apical membrane Na⁺-K⁺-2Cl^– symporter) and increased extrusion from the cell by the basalt- eral membrane Na⁺-K⁺-ATPase pump.
• Diseases of the adrenal cortex can alter aldosterone levels and thereby impair the ability of the kidneys to maintain Na⁺ balance and euvolemia.

“How do the kidneys maintain ECF volume balance?”

With decreased secretion of aldosterone (hypoaldosteronism), the reabsorption of Na⁺ by the aldosterone-sensitive distal nephron (late distal tubule and collecting duct) is reduced, and sodium chloride (NaCl) is lost in the urine.

• Because urinary NaCl loss can exceed the amount of NaCl ingested in the diet, negative Na⁺ balance ensues, and the extracellular fluid (ECF) volume decreases.
• In response to the ensuing ECF volume contraction, sympathetic tone is increased, and levels of renin, angiotensin 2, and arginine vasopressin are elevated.
• With increased aldosterone secretion (hyperaldosteronism), the opposite effects are observed: Na⁺ reabsorption by the aldosterone-sensitive distal nephron is enhanced and excretion of NaCl is reduced.

Consequently, ECF volume is increased, sympathetic tone is decreased, and the levels of renin, angiotensin 2, and arginine vasopressin are decreased.

• As described later in this chapter, atrial natriuretic peptide and brain natriuretic peptide levels also are elevated in this setting.
• As summarized, activation of the renin-angiotensin-aldosterone system, as occurs with ECF volume depletion, decreases the excretion of NaCl by the kidneys.
• Conversely, this system is suppressed by ECF volume expansion, thereby enhancing renal NaCl excretion.

Natriuretic Peptides

The body produces a number of substances, including ANP and BNP, that act on the kidneys to increase Na⁺ excretion.

• Of these substances, natriuretic peptides produced by the heart and kidneys are best understood and are the focus of the following discussion.
• The heart produces two natriuretic peptides. Atrial myocytes primarily produce and store the peptide hormone ANP, and ventricular myocytes primarily produce and store BNP.
• Both peptides are secreted in response to myocardial wall stretch (i.e., during cardiac dilatation that accompanies volume expansion and/or heart failure), and they act to relax vascular smooth muscle and promote NaCl and water excretion by the kidneys.
• The kidneys also produce a related natriuretic peptide termed urodilatin. Its actions are limited to promoting NaCl excretion by the kidneys.
• In general, the actions of these natriuretic peptides, as they relate to renal NaCl and water excretion, antagonize those of the renin-angiotensin-aldosterone system.

Natriuretic Peptide Actions Include:

1. Afferent arteriolar vasodilation and efferent arteriolar vasoconstriction within the glomerulus, increase the GFR and the filtered amount of Na⁺.
2. Inhibition of renin secretion by the juxtaglomerular cells of the afferent arterioles.
3. Inhibition of aldosterone secretion by the glomerulus cells of the adrenal cortex. This inhibition occurs by two mechanisms:
   • Inhibition of renin secretion by the juxtaglomerular cells, thereby reducing angiotensin II-induced aldosterone secretion, and
   • Direct inhibition of aldosterone secretion by the glomerulosa cells of the adrenal cortex.
4. Inhibition of NaCl reabsorption by the collecting duct, which also is caused in part by reduced levels of aldosterone. However, the natriuretic peptides also act directly on the collecting duct cells.
   • Through the second messenger, cyclic guanosine monophosphate, natriuretic peptides inhibit Na⁺ channels in the apical membrane and thereby decrease Na⁺ reabsorption.
   • This effect occurs predominantly in the medullary portion of the collecting duct.
5. Inhibition of AVP secretion by the posterior pituitary and AVP action on the collecting duct. These effects decrease water reabsorption by the collecting duct and thus increase the excretion of water in the urine.

“Role of the loop of Henle in NaCl concentration”

• These effects of the natriuretic peptides increase the net excretion of NaCl and water by the kidneys.
• Hypothetically, a reduction in the circulating levels of these peptides would be expected to decrease NaCl and water excretion, but convincing evidence for this effect has not been reported.

Arginine Vasopressin:

• As discussed, a decreased ECF volume stimulates AVP secretion by the posterior pituitary.
• The elevated levels of AVP decrease water and NaCl excretion by the kidneys, which serve to reestablish euvolemia.

Control Of Renal Nacl Excretion During Euvolemia

The maintenance of Na⁺ balance and therefore euvolemia requires the precise matching of the amount of NaCl ingested and the amount excreted from the body.

• As already noted, the kidneys are the major route for NaCl excretion. Accordingly, in a euvolemic person, we can equate daily urine NaCl excretion with daily NaCl intake.
• The amount of NaCl excreted by the kidneys can vary widely. Under conditions of salt restriction (i.e., a low NaCl diet), virtually no Na⁺ appears in the urine.
• Conversely, in persons who ingest large quantities of NaCl, renal Na⁺ excretion can exceed 1000 mEq/day. The kidneys require several days to respond maximally to variations in dietary NaCl intake.

During the transition period, excretion does not match intake, and the person is in either positive (intake > excretion) or negative (intake < excretion) Na⁺ balance.

• This phenomenon is illustrated. When Na⁺ balance is altered during these transition periods, the ECF volume changes in parallel.
• Water excretion, regulated by AVP, also is adjusted to keep plasma osmolality constant, effectively resulting in isosmotic changes in ECF volume.
• Thus with positive Na⁺ balance, the ECF volume expands, whereas with negative Na⁺ balance, the ECF volume contracts. In both cases, no change in plasma [Na⁺] occurs.

These changes in ECF volume can be detected by monitoring changes in body weight. Ultimately, renal excretion reaches a new steady state and NaCl excretion once again is matched to intake.

• The time course for the adjustment of renal NaCl excretion varies (from hours to days) and depends on the magnitude of the change in NaCl intake.
• Adaptation to large changes in NaCl intake requires a longer time than adaptation to small changes in intake.
• The general features of Na⁺ handling along the nephron must be understood to comprehend how renal Na⁺ excretion is regulated. (for the cellular mechanisms of Na⁺ transport along the nephron.)

“Impact of glomerular filtration rate (GFR) on ECF volume”

Most (67%) of the filtered amount of Na⁺ is reabsorbed by the proximal tubule. An additional 25% is reabsorbed by the thick ascending limb of the loop of Henle, and the remainder is largely reabsorbed by the distal tubule and collecting duct.

In a normal adult, the filtered amount of Na⁺ is approximately 25,000 mEq/day.

Filtered amount of Na⁺ = (GFR)(plasma [Na⁺])

= (180 L/day)(140 mEq/L)

= 25,200 mEq/day

With a typical diet, less than 1% of this filtered amount is excreted in the urine (approximately 140 mEq/day). Because of the large amount of filtered Na⁺, small changes in Na⁺ reabsorption by the nephron can profoundly affect Na⁺ balance and thus the volume of the ECF.

• For example, an increase in Na⁺ excretion from 1% to 3% of the filtered amount represents an additional loss of approximately 500 mEq/day of Na⁺.
• Because the ECF Na⁺ concentration is 140 mEq/L, such a Na⁺ loss would decrease the ECF volume by more than 3 L (i.e., water excretion would parallel the loss of Na⁺ to maintain body fluid osmolality constant: [500 mEq/day]/[140 mEq/L] = 3.6 L/ day of fluid loss).
• Such fluid loss in a person weighing 70 kg would represent a 26% decrease in the ECF volume.

In euvolemic subjects, the nephron segments distal to the loop of Henle, namely the distal tubule and collecting duct, are the main nephron segments where Na⁺ reabsorption is adjusted to maintain excretion at a level appropriate for dietary intake.

• However, this does not mean that the other portions of the nephron are not involved in this process.
• Because the reabsorptive capacity of the distal tubule and collecting duct is limited, the upstream segments of the nephron (i.e., the proximal tubule and loop of Henle) must reabsorb the bulk of the filtered amount of Na⁺.

Thus during euvolemia, Na⁺ handling by the nephron can be explained by two general processes:

1. Na⁺ reabsorption by the proximal tubule and loop of Henle is regulated so that a relatively constant portion of the filtered amount of Na⁺ is delivered to the distal tubule.
   • The combined action of the proximal tubule and loop of Henle reabsorbs approximately 92% of the filtered amount of Na⁺, and thus 8% of the filtered amount is delivered to the distal tubule.
2. Reabsorption of this remaining portion of the filtered amount of Na⁺ by the distal tubule and collecting duct is regulated so that the amount of Na⁺ excreted in the urine closely matches the amount ingested in the diet at a steady state.
   • Thus these later nephron segments make final adjustments in Na⁺ excretion to maintain the euvolemic state.

Mechanisms For Maintaining Constant Na⁺ Delivery To The Distal Tubule:

A number of mechanisms maintain delivery of a constant fraction of the filtered amount of Na⁺ to the beginning of the distal tubule.

• These processes are autoregulation of the GFR (a mechanism that keeps the filtered amount of Na⁺ constant), glomerulotubu-lar balance, and load dependence of Na⁺ reabsorption by the loop of Henle.
• Autoregulation of the GFR allows maintenance of a relatively constant filtration rate over a wide range of perfusion pressures. Because the filtration rate is constant, the delivery of filtered Na⁺ to the nephrons also is kept constant.

Despite the autoregulatory control of the GFR, small variations in GFR occur. If these changes were not compensated for by an appropriate adjustment in Na⁺ reabsorption by the nephron, Na⁺ excretion would change markedly.

“How does the renal system respond to sodium imbalance?”

• Fortunately, Na⁺ reabsorption in the euvolemic state, especially by the proximal tubule, changes in parallel with changes in the GFR. This phenomenon is termed glomerulotubular (G-T) balance.
• Thus if the GFR increases, the amount of Na⁺ reabsorbed by the proximal tubule increases proportionately. The opposite occurs if the GFR decreases.

The final mechanism that helps maintain the constant delivery of Na⁺ to the beginning of the collecting duct involves the ability of the loop of Henle to increase its reabsorptive rate in response to increased delivery of Na⁺.

Regulation Of Distal Tubule And Collecting Duct Na⁺ Reabsorption:

When delivery of Na⁺ is constant, small adjustments in the distal tubule and, to a lesser degree, collecting duct Na⁺ reabsorption is sufficient to balance excretion with intake.

• (As already noted, as little as a 2% change in fractional Na⁺ excretion produces more than a 3 L change in the volume of the ECF.) Aldosterone is the primary regulator of Na⁺ reabsorption by the distal tubule and collecting duct and thus of Na⁺ excretion under this condition.
• When aldosterone levels are elevated, Na⁺ reabsorption by these segments is increased (excretion is decreased). When aldosterone levels are decreased, Na⁺ reabsorption is decreased (excretion is increased).

In addition to aldosterone, a number of other factors, including natriuretic peptides, prostaglandins, uroguanylin, adrenomedullin, and sympathetic nerves, alter Na⁺ reabsorption by the distal tubule and collecting duct.

• However, the relative effects of these other factors on the regulation of Na⁺ reabsorption by these segments during euvolemia are unclear.
• As long as variations in the dietary intake of NaCl are minor, the mechanisms previously described can regulate renal Na⁺ excretion appropriately and thereby maintain euvolemia.
• However, these mechanisms cannot effectively handle significant changes in NaCl intake.
• When NaCl intake changes significantly, ECF volume expansion or ECF volume contraction occurs.
• In such cases, additional factors are invoked to act on the kidneys to adjust Na⁺ excretion and thereby reestablish the euvolemic state.

The excretion rate of Na⁺ by the kidneys can be quantitated in the following way:

⇒ \(\mathrm{U}_{\mathrm{Na}^{+}} \times \dot{\mathrm{V}}=\mathrm{GFR} \times \mathrm{P}_{\mathrm{Na}^{+}}-\mathrm{R}\)

where U_Na+ × V is the excretion rate in mEq/time (U_Na+ is the urine [Na⁺] and V is the urine flow rate), GFR X P_Na+ is the filtered amount of Na⁺ (GFR is the glomerular filtration rate and P_Na+ is the plasma [Na⁺]), and R is the amount of Na⁺ reabsorbed by the nephron.

“Pathophysiology of ECF volume imbalances explained”

Control Of Na⁺ Excretion With Volume Expansion

During ECF volume expansion, baroreceptors in both the high- and low-pressure vascular circuits send signals to the kidneys. These signals result in increased excretion of NaCl and water.

The signals acting on the kidneys include:

1. Decreased activity of the renal sympathetic nerves
2. Increased release of ANP and BNP from the heart and urodilatin by the kidneys
3. Inhibition of AVP secretion from the posterior pituitary and decreased AVP action on the collecting duct
4. Decreased renin secretion and thus decreased production of angiotensin 2
5. Decreased aldosterone secretion, which is a consequence of reduced angiotensin II levels, and elevated natriuretic peptide levels The integrated response of the nephron to these signals is illustrated.

Three general responses to ECF volume expansion occur (the numbers correlate with those circled:

“Emerging research on ECF volume regulation mechanisms”

The GFR increases. The GFR increases mainly as a result of the decrease in sympathetic nerve activity.

• Sympathetic fibers innervate the afferent and efferent arterioles of the glomerulus and control their diameter. Decreased sympathetic nerve activity leads to arteriolar dilation.
• Because afferent arteriolar dilation is greater than efferent dilation, the hydrostatic pressure within the glomerular capillary is increased, thereby increasing the filtration pressure and the GFR.
• Note that the corresponding filtration fraction decreases because the renal plasma flow increases to a greater degree than the GFR.

Natriuretic peptides, which are increased during ECF volume expansion, also promote an increase in GFR via differential direct effects on the afferent (vasodilation) and efferent (vasoconstriction) arterioles.

• With the increase in the GFR, the filtered amount of Na⁺ increases. The reabsorption of Na⁺ decreases in the proximal tubule and loop of Henle.
• Several mechanisms act to reduce Na⁺ reabsorption by the proximal tubule, but the precise role of each of these mechanisms remains unresolved.
• Because activation of the sympathetic nerve fibers that innervate this nephron segment stimulates Na⁺ reabsorption, the decreased sympathetic nerve activity that results from ECF volume expansion decreases Na⁺ reabsorption.

In addition, angiotensin 2 directly stimulates Na⁺ reabsorption by the proximal tubule. Because angiotensin 2 levels also are reduced by ECF volume expansion, proximal tubule Na⁺ reabsorption decreases accordingly.

• Increased hydrostatic pressure within the glomerular capillaries also increases the hydrostatic pressure within the peritubular capillaries.
• In addition, the decrease in filtration fraction reduces the peritubular oncotic pressure.
• These alterations in the capillary Starling forces reduce the absorption of solute (for example., NaCl) and water from the lateral intercellular space and thus reduce proximal tubular reabsorption.

Both the increase in the filtered amount of NaCl and the decrease in NaCl reabsorption by the proximal tubule result in the delivery of more NaCl to the loop of Henle.

• Because activation of the sympathetic nerves and aldosterone stimulates NaCl reabsorption by the loop of Henle, the reduced nerve activity and low aldosterone levels that occur with ECF volume expansion serve to reduce NaCl reabsorption by this nephron segment.
• Thus the fraction of the filtered amount delivered to the distal tubule is increased.
• Na⁺ reabsorption decreases in the distal tubule and collecting duct. As noted, the amount of Na⁺ delivered to the distal tubule exceeds that observed in the euvolemic state (the amount of Na⁺ delivered to the distal tubule varies in proportion to the degree of ECF volume expansion).

This increased amount of delivered Na⁺ can overwhelm the reabsorptive capacity of the distal tubule and the collecting duct, an effect heightened by the reduced reabsorptive capacity of these segments associated with increased circulating natriuretic peptides and decreased circulating aldosterone levels.

• The final component in the response to ECF vol-ume expansion is the excretion of water. As Na⁺ excretion increases, plasma osmolality begins to fall, which decreases the secretion of AVP.
• AVP secretion also is decreased in response to the elevated levels of natriuretic peptides. In addition, these natriuretic peptides inhibit the action of AVP on the collecting duct.
• Together, these effects decrease water reabsorption by the collecting duct and thereby increase water excretion by the kidneys.

Thus the excretion of Na⁺ and water occurs in concert; euvolemia is restored, and body fluid osmolality remains constant.

• The time course of this response (hours to days) depends on the magnitude of the ECF volume expansion.
• Thus if the degree of ECF volume expansion is small, the mechanisms just described generally restore euvolemia within 24 hours. However, with larger degrees of ECF volume expansion, the response can take several days.

In brief, the renal response to ECF volume expansion involves the integrated action of all parts of the nephron:

1. The filtered amount of Na⁺ is increased,
2. The proximal tubule and loop of Henle reabsorption is reduced (the glomerular filtration rate is increased and proximal reabsorption is decreased, and thus G-T balance does not occur under this condition), and
3. The delivery of Na⁺ to the distal tubule is increased. This increased delivery, along with the inhibition of distal tubule and collecting duct reabsorption, results in the excretion of a larger fraction of the filtered amount of Na⁺ and thus restores euvolemia.

“Case studies on ECF volume and NaCl balance outcomes”

Control Of Na⁺ Excretion With Volume Contraction

During ECF volume contraction, volume sensors in both the high- and low-pressure vascular circuits send signals to the kidneys that reduce NaCl and water excretion. The signals that act on the kidneys include:

1. Increased renal sympathetic nerve activity
2. Increased secretion of renin, which results in elevated angiotensin II levels and thus increased secretion of aldosterone by the adrenal cortex
3. Stimulation of AVP secretion by the posterior pituitary

The integrated response of the nephron to these signals is illustrated. The general response is as follows

“Global prevalence of ECF volume disorders”

• The GFR decreases. Afferent and efferent arteriolar constriction occurs as a result of increased renal sympathetic nerve activity.
• The effect is greater on the afferent than on the efferent arteriole. This vasoconstriction causes the hydrostatic pressure in the glomerular capillary to fall and thereby decreases the GFR.
• The filtration fraction increases because the renal plasma flow decreases more than the GFR, but the absolute decrease in the GFR reduces the filtered load of Na⁺.

Na⁺ reabsorption by the proximal tubule and loop of Henle is increased. Several mechanisms augment Na⁺ reabsorption in the proximal tubule.

• For example, increased sympathetic nerve activity and angiotensin II levels directly stimulate Na⁺ reabsorption.
• The decreased hydrostatic pressure within the glomerular capillaries also leads to a decrease in the hydrostatic pressure within the peritubular capillaries.
• In addition, the increased filtration fraction results in an increase in the peritubular oncotic pressure.

These alterations in the capillary Starling forces facilitate the movement of fluid from the lateral intercellular space into the capillary and thereby stimulate the reabsorption of solute (for example., NaCl) and water by the proximal tubule.

• The reduced amount of filtered Na⁺ and enhanced proximal tubule reabsorption decrease the delivery of Na⁺ to the loop of Henle.
• Increased sympathetic nerve activity, as well as elevated levels of angiotensin 2 and aldosterone, stimulate Na⁺ reabsorption by the thick ascending limb.
• Because sympathetic nerve activity is increased and angiotensin 2 and aldosterone levels are elevated during ECF volume contraction, increased Na⁺ reabsorption by this segment is expected. Thus less Na⁺ is delivered to the distal tubule.

Na⁺ reabsorption by the distal tubule and collecting duct is enhanced. The small amount of Na⁺ that is delivered to the distal tubule is almost completely reabsorbed because transport in this segment and the collecting duct is enhanced.

• This stimulation of Na⁺ reabsorption by the distal tubule and collecting duct is induced by increased angiotensin 2 and aldosterone levels (increased sympathetic nerve activity also will stimulate Na⁺ reabsorption).
• Finally, water reabsorption by the late portion of the distal tubule and the collecting duct is enhanced by AVP (AVP also stimulates limited Na⁺ reabsorption in the late distal tubule and collecting duct), the levels of which are elevated through activation of the low high-pressure vascular volume sensors and by the elevated levels of angiotensin 2.
• As a result, water excretion is reduced.

Because both water and Na+ are retained by the kidneys in equal proportions, euvolemia is reestablished and body fluid osmolality remains constant.

• The time course of this expansion of the ECF (hours to days) and the degree to which euvolemia is attained depend on the magnitude of the ECF volume contraction and the dietary intake of Na+.
• Thus the kidneys reduce Na+ excretion and euvolemia can be restored more quickly if additional NaCl is ingested in the diet.

In brief, the nephron’s response to ECF volume contraction involves the integrated action of all its segments:

1. The filtered amount of Na+ is decreased,
2. Proximal tubule and loop of Henle reabsorption is enhanced (the GFR is decreased and proximal reabsorption is increased and thus G-T balance does not occur under this condition), and
3. The delivery of Na+ to the distal tubule is reduced. This decreased delivery, together with enhanced Na+ reabsorption by the distal tubule and collecting duct, virtually eliminates Na+ from the urine.

Edema

Edema is the accumulation of excess fluid within the interstitial space. As described, Starling forces across the capillary wall determine the movement of fluid into and out of the vascular compartment in exchange with the extravascular interstitial compartment.

• Alterations of these forces under pathologic conditions can lead to increased movement of fluid from the vascular space into the interstitium, resulting in edema formation.
• The role of the kidneys in the formation of edema can be appreciated by recognizing that the interstitial compartment typically must contain 2 to 3 L of excess fluid before edema is clinically evident (for example., swelling of the ankles).

The source of this fluid is the vascular compartment (i.e., plasma), which has a volume of 3 to 4 L in healthy persons.

• Alterations in the Starling forces that would accompany a 2 to 3 L fluid shift out of the vascular compartment into the interstitial compartment would be predicted to limit such marked fluid movement and the decline in blood pressure that would attend such a marked fluid shift.
• However, retention of NaCl and water by the kidneys maintains intravascular compartment volume, thereby maintaining the blood pressure and facilitating interstitial fluid redistribution and edema development.

Alterations In Starling Forces:

In the Starling forces and their effect on fluid movement across the capillary wall were explained.

• Edema results from changes in the Starling forces that alter these fluid dynamics.
• Recall that fluid movement across a capillary wall is driven by hydrostatic and oncotic pressure gradients:

Filtration rate = K_f[(P_c — P_i) — a( π_c —π_i)]

where K_f is the filtration coefficient of the capillary wall (a measure of the intrinsic wall permeability and the surface area available for fluid flow), and P_c and P_i are the hydrostatic pressures within the lumen of the capillary.

The interstitium, respectively, σ is the reflection coefficient for protein across the capillary wall (approximately 0.9 for skeletal muscle), and π_c and π_i are the oncotic pressures generated by protein within the capillary lumen and the interstitium, respectively.

Capillary Hydrostatic Pressure (P_c)

Increasing the Pc favors the movement of fluid out of the capillary or retards its movement into the capillary, thereby promoting edema formation.

• Normally the resistance of the precapillary arteriole is well regulated such that changes in systemic blood pressure do not result in marked alterations in P_c.
• However, postcapillary resistance is not regulated to the same degree, and thus alterations in the pressure within the venous side of the circulation have significant effects on P_c.
• Consequently, an increase in the venous pressure elevates P_c, which increases the movement of fluid into the interstitium, resulting in the accumulation of edema fluid.
• Common causes for increased venous pressure include venous thrombosis and congestive heart failure.

Plasma Oncotic Pressure (π_c):

A decrease in π_c would be expected to favor the movement of fluid out of the capillary lumen and inhibit its reabsorption from the interstitium.

• Because albumin is the most abundant plasma protein, alterations in nc result primarily from changes in the plasma [albumin].
• However, it is important to remember that changes in plasma protein concentration result in parallel changes in the protein concentration of the interstitial fluid.
• This phenomenon reflects the fact that the reflection coefficient for protein is 0.9 and thus proteins can cross the capillary wall.
• Because of the parallel changes in capillary and interstitial fluid protein concentration, the oncotic pressure gradient across the capillary wall (π_c – π_i) may not change appreciably.

Lymphatic Obstruction:

As noted , the lymphatic system serves to return interstitial fluid formed by capillary filtration to the vascular system.

• Obstruction of a lymphatic duct interferes with this process, and as a result, interstitial fluid accumulates in the portion of the body drained by the obstructed duct (i.e., edema forms).
• As this interstitial fluid accumulates, the interstitial hydro-static pressure increases, and eventually a new steady state is reached where the Starling forces are once again balanced and no additional fluid accumulates.
• However, unless the obstruction is corrected, the area. Edema can be classified as localized or generalized.

Localized edema, as the name denotes, represents the abnormal accumulation of interstitial fluid in a specific area or region of the body.

• Common causes of localized edema include insect stings and lymphatic obstruction.
• The venom of many stinging or biting insects contains substances that either directly increase capillary permeability or cause the release of mediators of inflammation that have a similar effect.
• In addition, the venom or inflammatory mediators may cause vasodilation. Increasing the permeability of the capillary, or in some cases the postcapillary venule, increases the filtration coefficient (Kf) and also can decrease the protein reflection coefficient.

Both effects can increase fluid movement out of the capillary, with the latter effect also altering the Starling forces by changing the protein oncotic pressure gradient.

• Starling forces are further altered in response to the vasodilation (i.e., capillary hydrostatic pressure [Pc] is increased).
• The net effect of these changes is that more fluid moves out of the capillary into the interstitium and localized swelling occurs.

Lymphatic obstruction often accompanies surgical treatment of tumors. For example, in some women with breast cancer, regional lymph nodes that drain the affected breast are surgically removed.

• When those located in the axilla are removed, the draining of lymph from that arm may be impaired. As a result, edema may develop in the arm.
• Generalized edema results when Starling forces across all capillary beds are altered. Edema may be present in the lungs (i.e., pulmonary edema) or throughout the systemic circulation (i.e., peripheral edema).

Peripheral edema is most commonly observed in the feet, ankles, and legs, where the force of gravity magnifies the changes in Starling forces (i.e., further increases P_c) and thereby causes more fluid to leave the capillary and enter the interstitium.

• One of the most common causes of generalized edema is congestive heart failure.
• In this condition, blood accumulates in the venous side of the circulation, raising P_c, which in turn causes fluid to move out of the capillary into the interstitium.

Generalized edema is also seen with renal diseases associated with the nephrotic syndrome.

• In the nephrotic syndrome, glomerular capillary permeability is altered, allowing large quantities of albumin to be lost in the urine (albuminuria).
• If the rate of loss exceeds the rate at which albumin is synthesized by the liver, the plasma [albumin] falls.

The reduction in plasma protein concentration, and thus nc, was thought to be the primary cause of edema formation in patients with nephrotic syndrome.

• Because the oncotic pressure gradient across the capillary wall may not change appreciably (i.e., interstitial protein oncotic pressure also falls), it is likely that other factors are responsible for, or at least contribute to, the abnormal accumulation of fluid in the interstitial compartment.
• Supporting this notion is the observation that edema does not spontaneously develop in rats deficient in albumin. It is now known that one of these other factors is primary NaCl retention by the distal tubule and collecting duct.

With damage to the glomerular filtration barrier, the serum protein plasminogen enters the renal tubules where it is cleaved to form plasmin by the serine protease urokinase (produced by proximal tubule cells).

• Plasmin, also a serine protease, then cleaves the y-subunit of the epithelial Na⁺ channels present in the apical membrane of cells in the late distal tubule and collecting duct, thereby increasing the open time of these channels.
• This phenomenon results in increased Na⁺ (and Cl^–) reabsorption. The ensuing retention of NaCl (along with water) increases vascular volume and thereby leads to an increase in P_c, increased movement of fluid into the interstitial compartment, and thus edema formation.

Drained by the obstructed lymphatic duct remains edematous even in this new steady state.

Capillary Permeability:

• An increase in capillary permeability favors increased movement of fluid across the capillary wall and thus accumulation of excess fluid in the interstitial compartment.
• The increased permeability also can alter the capillary reflection coefficient for protein(s), allowing more protein across the capillary and thus altering the protein oncotic pressure gradient
  (π_c-π_i).

Role Of The Kidneys:

The role of the kidneys in edema-forming states is best illustrated by considering the situation that exists with heart failure. Because of decreased cardiac performance, venous pressure is elevated, and perfusion of the kidneys is impaired.

“Complications of ignoring ECF volume issues”

• The increase in venous pressure alters the Starling forces (i.e., increased Pc) and causes fluid to accumulate in the interstitium.
• At the same time, decreased cardiac performance (decreased cardiac output and blood pressure) reduces the ECV, which is misinterpreted by the body’s vascular volume sensors as a decrease in ECF volume.
• The fall in ECF volume activates the renal sympathetic nerves and the renin-angiotensin-aldo-sterone system and causes AVP secretion. In response to these signals, the kidneys retain NaCl and water, as already described.

This retention of isotonic fluid expands the ECF volume and thus blood volume, thereby helping perpetuate a vicious cycle of fluid accumulation that can further exacerbate congestive heart failure.

• Intravascular volume expansion also contributes to the increased Pc, increased interstitial fluid accumulation, and edema formation.
• As fluid begins to accumulate in the interstitium, it is taken up by the lymphatics and returned to the systemic circulation. As noted, thoracic duct and right lymphatic duct flow is approximately 1 to 4 L/day.
• The lymphatic system can increase this flow up to 20 L/day. Because a significant amount of lymph returns to the circulation at the level of regional lymph nodes, the actual amount of interstitial fluid returned to the systemic circulation by the lymphatic system can exceed 20 L/day.

Nevertheless, the capacity of the lymphatic system has a limit. When this limit is reached, edema fluid begins to accumulate.

• The importance of NaCl retention by the kidneys in edema formation provides two approaches for treatment. The first involves dietary manipulation. The ultimate source of NaCl is the diet.
• Thus if dietary intake of NaCl is restricted, the amount that can be retained by the kidneys is reduced and edema formation is limited. The second approach is to inhibit the kidneys’ ability to retain NaCl.
• This inhibition is accomplished clinically by the use of diuretics, which, as described, inhibit Na⁺ transport mechanisms in the nephron. Thus NaCl excretion is increased and NaCl retention is blunted.

The post Regulation Of Extracellular Fluid Volume And Nacl Balance appeared first on BDS Notes.

1. What is this specimen?

• Specimen of lymph nodes that are matted. The cut surface shows caseation. Hence, it is tuberculous lymphadenitis.

“What is tuberculous lymphadenitis?”

2. What is the microscopic picture?

• Central caseation is surrounded by epithelioid cells, Langhans type of giant cells.

3. What are the stages of TB lymphadenitis?

• Stage of lymphadenitis
• Stage of matting
• Stage of cold abscess
• Stage of collar stud abscess
• Stage of sinus formation

4. Why is matting seen in TB lymphadenitis?

• It is because of periodontitis.

5. What is the treatment of cold abscess?

• Nondependent aspiration by using a wide bore needle, to avoid sinus formation.

“Understanding TB lymphadenitis: Causes and symptoms”

Lymphoma

1. What is the diagnosis?

• Multiple lymph nodes which are discrete and not matted. The Cut surface does not show caseation. It is homogenous. Hence, this is a specimen of Hodgkin’s lymphoma.

2. How do you confirm the diagnosis?

• Lymph node biopsy.

3. What is the microscopic picture?

• Cellular pleomorphism: Lymphocytes, histiocytes, eosinophils, monocytes with giant cells containing mirror image nuclei—Reed-Sternberg cell.

4. What are the common lymph nodes involved in Hodgkin’s lymphoma?

• Cervical, axillary, para-aortic, iliac, and inguinal lymph nodes,

5. Is Waldeyer’s ring involvement seen in Hodgkin’s lymphoma?

• No. It is usually seen in non-Hodgkin’s lymphoma.

“Importance of specimen collection in TB lymphadenitis”

Marjolin’s Ulcer

1. What is this specimen?

• Wide excision specimen, showing ulcerated growth arising from the scar. It has everted edges, and there is extensive scarring.

2. What is the diagnosis?

• Squamous cell carcinoma arising in scar tissue is called Marjolin’s ulcer

3. What are the common causes of Marjolin’s ulcer?

• Burns, snake bite, and varicose ulcer

“Complications of untreated TB lymphadenitis”

4. What are the peculiarities of Marjolin’s ulcer?

• It grows very slowly because of scar tissue.
• It is painless as nerves have been destroyed.
• It does not spread by lymphatics as they are also destroyed.

5. What is the treatment?

• Wide excision followed by split skin grafting.

“Common types of specimens used for TB lymphadenitis diagnosis”

Squamous Cell Carcinoma

1. What is this specimen?

• Specimen of wide excision showing ulcerated growth with everted edges arising from skin.

2. What is the diagnosis?

• Squamous cell carcinoma

3. What is the microscopic picture?

• Mitotic figures with keratin pearls or epithelial pearls.

4. What is the other treatment for squamous cell carcinoma?

• Radiotherapy

5. What are the common causes of squamous cell carcinoma?

• Leukoplakia
• Radiation dermatitis
• Bowen’s disease
• Congenital skin conditions like xeroderma pigmentosa and albinism
• Chronic scar

“Impact of culture tests on TB lymphadenitis diagnosis”

Specimen Of Hemiglossectomy With Hemimandibulectomy

1. What is this specimen?

• Specimen showing growth arising from the tongue and infiltrating the mandible

2. What is the diagnosis?

• Advanced carcinoma tongue

3. Is radiotherapy indicated in this situation?

• No, because the chances of radionecrosis of the mandible are high.

“Role of histopathology in analyzing TB lymphadenitis specimens”

4. What type of X-ray is taken to look for involvement of the mandible?

• Orthopantomogram

5. What is Commando’s operation?

• Hemiglossectomy with excision of the floor of the mouth, hemimandibulectomy, with radical block dissection of the neck done in a single stage, with en bloc removal.

The post Specimens Tuberculous (Tb) Lymphadenitis appeared first on BDS Notes.

Lacrimal Gland Parts

1. Lacrimal gland and its duct:

1. Lacrimal gland:
   • Lacrimal gland is serous ‘J’ shaped gland
     Lacrimal gland Site:
   • In the lacrintal fossa on the anterolateral part of the roof of the bony orbit & partly on the upper eyelid
     Lacrimal gland Parts:
   • Orbital part: larger & deeper
   • Palpebral part: smaller & superficial
2. Lacrimal duct:
   • Lacrimal duct pierces the conjunctiva of the upper eyelid, open into the conjunctival sac at the superior fornix
   • Most of the ducts of orbital part pass through the palpebral part

“Understanding the structures forming the lacrimal apparatus through FAQs: Anatomy, functions, and uses explained”

Conjunctival Sac

1. Palpebral conjunctiva:
   • Lines the deep surface of eyelids
   • Palpebral conjunctiva is thick, opaque, highly vascular & adherent to tarsal plate
2. Bulbar conjunctiva:
   • Lines the front of eyeball
   • Bulbar conjunctiva is thin, transparent & loosely attached to eyeball
   • Conjunctival Ssac is the potential space between bulbar & palpebral part
3. Conjunctival fornices:
   • The lines along which the palpebral conjunctiva of the upper & lower eyelids is reflected on eyeball

“Importance of studying the lacrimal apparatus for medical students: Questions explained”

Lacrimal puncta & canaliculi

• Lacrimal canaliculi is 10 mm long structure beginning at lacrimal punctum
• Lacrimal canaliculi has
  • 2 mm long vertical part
  • 8 mm long horizontal part
• Lacrimal canaliculi has dilated ampulla at the bend
  • Opening
• In the lateral wall of the lacrimal sac behind medial palpebral ligament

4. Lacrimal Sac:

• Lacrimal Sac Site: lacrimal groove behind medial palpebral ligament
• Lacrimal Sac Size: 12 mm long & 5 mm wide
  Lacrimal Sac Parts:
• Upper end is blind
• Lower end continuous with nasolacrimal duct
  Lacrimal Sac Relations:
• Anteriorlymedial palpebral ligament, orbicularis oculi
• Mediallylacrimal groove
• Laterallylacrimal fascia & lacrimal part of orbicularis oculi

“Common challenges in mastering lacrimal apparatus notes effectively: FAQs provided”

5. Nasolacrimal Duct:

• Nasolacrimal Duct is 18 mm long membranous passage
  Nasolacrimal Duct Course:
• Begins at lower end of lacrimal sac
• Runs downwards, backwards & laterally
• Opens into inferior meatus of nose

Valve of Hasner:

• Valve of Hasner is a fold of mucous membrane forming imperfect valve at lower end of duct

Valve of Hasner Nerve Supply:

“Factors influencing success with lacrimal apparatus studies: Q&A”

The post Structures Forming Lacrimal Apparatus appeared first on BDS Notes.

“What are the branches of the facial artery? A detailed question and answers guide”

Facial Artery Origin

• Facial Artery  is branch of external carotid artery
• Given off in the carotid triangle just above the tip of greater cornua of hyoid bone

Facial Artery Course:

• Facial Artery  runs first in the neck as cervical part
• Then on the face as facial part
• Both parts are very tortuous
• Facial Artery  winds around the base of mandible, pierce the deep cervical fascia at the anteroinferior angle of masseter muscle and enters the face
• Facial Artery  Starts: at 25 cm lateral to the angle of the mouth
• Facial Artery  Ascends: By side of nose upto medial angle of eye
• Facial Artery  Terminates: By supplying lacrimal sac
• Facial Artery  Anastomose: With dorsal nasal branch of the ophthalmic artery

Facial Artery Branches:

“Understanding branches of the facial artery through FAQs: Anatomy, functions, and uses explained”

Arterial Supply and Venous Drainage of Face

• The face is richly vascular.

Venous Drainage of Face Arterial supply:

1. Facial artery
   • Facial artery is chief artery of face
     Branch of:
   • External carotid artery given off in carotid triangle

Venous Drainage of Face Branches:

1. Anterior branches

“Importance of studying branches of the facial artery for medical students: Questions explained”

2. Posterior branches

• They are small and unnamed

3. Transverse facial artery

• It is small artery
  Branch of:
  • Superficial temporal artery
• Structures supplied by it
• • Parotid gland and its duct
  • Masseter and the overlying skin
  • Anastomose with neighbouring arteries

4. Arteries that accompany the cutaneous nerves

• These are small branches of ophthalmic, maxillary and superficial temporal artery.

Venous Drainage:

• Veins of the face communicates with the cavernous sinus.

“Common challenges in mastering facial artery anatomy effectively: FAQs provided”

Buccinator Muscle

Buccinator Muscle Origin:

• Upper fibres from maxilla opposite molar teeth
• Lower fibres from mandible opposite molar teeth
• Middle fibres from pterygomandibular raphe

Buccinator Muscle Insertion:

• Upper fibres straight to the upper lip
• Lower fibres straight to the lower lip
• Middle fibres decussate before passing to the lips

“Role of the external carotid artery as the origin of the facial artery: Questions answered”

Buccinator Muscle Action:

• Flattens cheek against gums & teeth
• Prevents accumulation of food in the vestibule
• It is a whistling muscle

Buccinator Muscle Examination:

• Puffing the mouth and then blowing forcibly as in whistling

Buccinator Muscle Nerve Supply:

• Buccal branch of facial nerve

Buccinator Muscle Applied Anatomy:

• In infranuclear lesions of the facial nerve, (Bell’s palsy) buccinators muscle is effected
• It leads to inability to blow the cheek & food accumulation between teeth & cheek.

“Factors influencing success with facial artery studies: Q&A”

Cutaneous innervations of face. (or) Mention the sensory nerve supply to the face.

“Steps to explain facial artery anatomy: Origin vs course vs termination: Q&A guide”

The post Branches of Facial Artery appeared first on BDS Notes.

• Scalp is the soft tissue which covers the calvaria of the skull

Scalp Layers:

S-Skin:

• S-Skin is outermost layer
• S-Skin is thick and hairy
• S-Skin is adherent to the epicranial
• S-Skin contains large number of hairs, sweat glands, sebaceous gland and is richly supplied by blood vessels

C-Superficial fascia:

• C-Superficial fascia is second layer
• C-Superficial fascia is more fibrous and dense in the center than periphery
• C-Superficial fascia contains large blood vessels & nerves of the scalp
• Thus C-Superficial fascia provides the proper medium for passage of vessels and nerves to the skin

A-Epicranial Aponeurosis:

• A-Epicranial Aponeurosis is freely movable

“Understanding the layers of the scalp through FAQs: Anatomy, functions, and uses explained”

Scalp Attachments:

• Anteriorly: Insertion of frontalis
• Posteriorly: Insertion of occipitalis
• In between occipital bellies: Extrernal occipital protuberance & highest nuchal lines
• Each side: Attached to superior temporal line

L-Loose areolar tissue:

• L-Loose areolar tissue contains emissary veins devoid of valves
• This communicates the veins of scalp with intracranial venous sinuses

Extent:

• Anteriorly: Eyelids
• Posteriorly: Highest & superior nuchal lines
• Each side: Superior temporal lines

P-Pericranium: Fifth layer

• Loosely attached to bony surfaces
• Firmly adherent to bony sutures
• P-Pericranium: Fifth layer is the outer periosteum of skull Emissary vein

“Importance of studying the layers of the scalp for medical students: Questions explained”

“Common challenges in mastering layers of the scalp notes effectively: FAQs provided”

Blood Supply Arterial Supply:

“Why is identifying the layers of the scalp critical for surgical procedures? Answered”

Venous Drainage:

Lymphatic Drainage:

“Factors influencing success with scalp anatomy studies: Q&A”

Nerve Supply:

“Steps to explain the layers of the scalp: Skin vs subcutaneous tissue vs galea aponeurotica vs loose connective tissue vs pericranium: Q&A guide”

Applied Anatomy According to layers:

Skin:

• Common site of sebaceous cyst due to abundant sebaceous glands
  • Superficial fascia
• Avulsed portion need not be cut away due to rich blood supply
• In open wound the vessels present in this layer are unable to retract & thus produce profuse bleeding
• Inflammation leads to little swelling but much pain
  • Loose areolar tissue
• Dangerous area of scalp as emissary vein open here
• If blood is collected in this layer, it leads to generalized swelling
  • Epicranial aponeurosis
• Wounds of scalp donot gape unless this layer is divided transversely
  • Pericranium
• Collection of fluid deep to it leads to cephalhaematoma

The post Layers of Scalp appeared first on BDS Notes.